Nlrp3 modulators

ABSTRACT

This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or drug combination of the compound) that modulate (e.g., agonizes or partially agonizes) NLRP3 that are useful, e.g., for treating a condition, disease or disorder in which an increase in NLRP3 signaling may correct a deficiency in innate immune activity (e.g., a condition, disease or disorder associated with an insufficient immune response) that contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g., cancer) in a subject (e.g., a human). This disclosure also features compositions as well as other methods of using and making the same.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/693,420, filed Nov. 25, 2019, which is a divisional application ofpatent application Ser. No. 15/898,258, filed Feb. 16, 2018, now U.S.Pat. No. 10,533,005, which claims the priority benefit of U.S.Provisional Application No. 62/460,677, filed Feb. 17, 2017, U.S.Provisional Application No. 62/490,881, filed Apr. 27, 2017, and U.S.Provisional Application No. 62/573,991, filed Oct. 18, 2017; thecontents of which are herein incorporated by reference in theirentirety.

TECHNICAL FIELD

This disclosure features chemical entities (e.g., a compound or apharmaceutically acceptable salt, and/or hydrate, and/or cocrystal,and/or drug combination of the compound) that modulate (e.g., agonizesor partially agonizes) NLRP3 that are useful, e.g., for treating acondition, disease or disorder in which an increase in NLRP3 signalingmay correct a deficiency in innate immune activity that contributes tothe pathology and/or symptoms and/or progression and/or treatmentrefractory state of the condition, disease or disorder (e.g., cancerswith low T-cell infiltration) in a subject (e.g., a human). Thisdisclosure also features compositions as well as other methods of usingand making the same.

BACKGROUND

Nucleotide-binding oligomerization domain-like receptors (“NLRs”)include a family of intracellular receptors that detectpathogen-associated molecular patterns (“PAMPs”) and endogenousmolecules (see, e.g., Ting, J. P. Y. et al., “The NLR gene family: astandard nomenclature,” Immunity, 28(3):285-287, (2008)).

NLRPs represent a subfamily of NLRs that include a Pyrin domain and areconstituted by proteins such as NLRP1, NLRP3, NLRP4, NLRP6, NLRP7, andNLRP12. NLRPs are believed to be involved with the formation ofmultiprotein complexes termed inflammasomes (see, e.g., Chaput, C. etal., “NOD-like receptors in lung diseases,” Frontiers in Immunology, 4:article 393, (2013)). These complexes typically include one or two NLRproteins, the adapter molecule apoptosis associated speck-likecontaining a CARD domain (ASC) and pro-caspase-1 F (see, e.g.,Bauemfeind, F and Homung, V. “Of inflammasomes and pathogens-sensing ofmicrobes by the inflammasome,” EMBO Molecular Medicine, 5(6):814-826,(2013)).

One such inflammasome is formed by the NLRP3 scaffold, the ASC adaptorand pro-caspase-1 (see, e.g., Hirota, J. A., et al., “The airwayepithelium nucleotide-binding domain and leucine-rich repeat protein 3inflammasome is activated by urban particulate matter,” Journal ofAllergy and Clinical Immunology, 129(4):1116.e6-1125.e6, (2012)), andits expression is believed to be induced by inflammatory cytokines andTLR agonists in myeloid cells and human bronchial epithelial cells(Id.). The NLRP3 inflammasome is believed to mediate thecaspase-1-dependent conversion of pro-IL-1β and pro-IL-18 to IL-1β andIL-18. Further, IL-1β and IL-18 have potential in the treatment ofvarious types of cancer (see, e.g., Chen, L-C. et al., EMBO Mol Med.,4(12):1276-1293 (2012) and Tse, B. W-C. et al., PLoS One, 6(9):e24241(2011)). IL-18 has been shown to override resistance to checkpointinhibitors in colon cancer animal tumor models (see e.g., Ma, Z. et al.,Clin. Cancer Res. January 11. (2016) DOI:10.1158/1078-0432.CCR-15-1655).

SUMMARY

This disclosure features chemical entities (e.g., a compound or apharmaceutically acceptable salt, and/or hydrate, and/or cocrystal,and/or drug combination of the compound) that modulate (e.g., agonizesor partially agonizes) NLRP3 that are useful, e.g., for treating acondition, disease or disorder in which an increase in NLRP3 signalingmay correct a deficiency in innate immune activity contributes to thepathology and/or symptoms and/or progression and/or treatment refractorystate of the condition, disease or disorder (e.g., cancers with lowT-cell infiltration) in a subject (e.g., a human). This disclosure alsofeatures compositions as well as other methods of using and making thesame.

An “agonist” of NLRP3 includes compounds that, at the protein level,directly bind or modify NLRP3 such that an activity of NLRP3 isincreased, e.g., by activation, stabilization, altered distribution, orotherwise.

Certain compounds described herein that agonize NLRP3 to a lesser extentthan a NLRP3 full agonist can function in assays as antagonists as wellas agonists. These compounds antagonize activation of NLRP3 by a NLRP3full agonist because they prevent the full effect of NLRP3 interaction.However, the compounds also, on their own, activate some NLRP3 activity,typically less than a corresponding amount of the NLRP3 full agonist.Such compounds may be referred to as “partial agonists of NLRP3”.

In some embodiments, the compounds described herein are agonists (e.g.full agonists) of NLRP3. In other embodiments, the compounds describedherein are partial agonists of NLRP3.

Generally, a receptor exists in an active (Ra) and an inactive (Ri)conformation. Certain compounds that affect the receptor can alter theratio of Ra to Ri (Ra/Ri). For example, a full agonist increases theratio of Ra/Ri and can cause a “maximal”, saturating effect. A partialagonist, when bound to the receptor, gives a response that is lower thanthat elicited by a full agonist (e.g., an endogenous agonist). Thus, theRa/Ri for a partial agonist is less than for a full agonist. However,the potency of a partial agonist may be greater or less than that of thefull agonist.

In one aspect, compounds of Formula I, or a pharmaceutically acceptablesalt thereof, are featured:

in which R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ can be as defined anywhereherein.

In one aspect, methods for modulating (e.g., agonizing, partiallyagonizing, antagonizing) NLRP3 activity are featured that includecontacting NLRP3 with a chemical entity described herein (e.g., acompound described generically or specifically herein or apharmaceutically acceptable salt thereof or compositions containing thesame). In preferred embodiments, methods for modulating NLRP3 activityare agonizing and partially agonizing. In certain embodiments, methodsfor modulating NLRP3 activity are agonizing. In certain embodiments,methods for modulating NLRP3 activity are partially agonizing. Methodsinclude in vitro methods, e.g., contacting a sample that includes one ormore cells comprising NLRP3 (e.g., THP-1 cells) with the chemicalentity. Methods can also include in vivo methods; e.g., administeringthe chemical entity to a subject (e.g., a human) having a disease inwhich an increase in NLRP3 signaling may correct a deficiency in innateimmune activity that contributes to the pathology and/or symptoms and/orprogression of the disease (e.g., cancer; e.g., a refractory cancer).

In some embodiments, compounds of the invention are useful for treatinga condition, disease or disorder in which a decrease in NLRP3 activity(e.g., a condition, disease or disorder associated with repressed orimpaired NLRP3 signaling) contributes to the pathology and/or symptomsand/or progression of the condition, disease or disorder (e.g., cancer)in a subject (e.g., a human).

A cancer is said to be refractory when it does not respond to (or isresistant to) cancer treatment. Refractory cancer is also known asresistant cancer.

In another aspect, methods of treating cancer are featured that includeadministering to a subject in need of such treatment an effective amountof a chemical entity described herein (e.g., a compound describedgenerically or specifically herein or a pharmaceutically acceptable saltthereof or compositions containing the same). In some embodiments, thecancer may be a refractory cancer

In a further aspect, methods of treatment of a disease in which anincrease in NLRP3 signaling may correct a deficiency in innate immuneactivity that contributes to the pathology and/or symptoms and/orprogression of the disease are featured that include administering to asubject in need of such treatment an effective amount of a chemicalentity described herein (e.g., a compound described generically orspecifically herein or a pharmaceutically acceptable salt thereof orcompositions containing the same).

In another aspect, methods of treatment are featured that includeadministering to a subject having a disease in which an increase inNLRP3 signaling may correct a deficiency in innate immune activity thatcontributes to the pathology and/or symptoms and/or progression of thedisease an effective amount of a chemical entity described herein (e.g.,a compound described generically or specifically herein or apharmaceutically acceptable salt thereof or compositions containing thesame).

In a further aspect, methods of treatment that include administering toa subject a chemical entity described herein (e.g., a compound describedgenerically or specifically herein or a pharmaceutically acceptable saltthereof or compositions containing the same), wherein the chemicalentity is administered in an amount effective to treat a disease inwhich an increase in NLRP3 signaling may correct a deficiency in innateimmune activity that contributes to the pathology and/or symptoms and/orprogression of the disease, thereby treating the disease.

Embodiments can include one or more of the following features.

The chemical entity can be administered in combination with one or moreadditional cancer therapies (e.g., surgery, radiotherapy, chemotherapy,toxin therapy, immunotherapy, cryotherapy or gene therapy, or acombination thereof; e.g., cancer therapies that include administeringone or more (e.g., two, three, four, five, six, or more) additionalanti-cancer agents. Non-limiting examples of additional anti-canceragents (chemotherapeutic agents) are selected from an alkylating agent(e.g., cisplatin, carboplatin, mechlorethamine, cyclophosphamide,chlorambucil, ifosfamide and/or oxaliplatin); an anti-metabolite (e.g.,azathioprine and/or mercaptopurine); a terpenoid (e.g., a vinca alkaloidand/or a taxane; e.g., Vincristine, Vinblastine, Vinorelbine and/orVindesine Taxol, Pacllitaxel and/or Docetaxel); a topoisomerase (e.g., atype I topoisomerase and/or a type 2 topoisomerase; e.g., camptothecins,such as irinotecan and/or topotecan; amsacrine, etoposide, etoposidephosphate and/or teniposide); a cytotoxic antibiotic (e.g., actinomycin,anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin,epirubicin, bleomycin, plicamycin and/or mitomycin); a hormone (e.g., alutenizing hormone releasing hormone agonist; e.g., leuprolidine,goserelin, triptorelin, histrelin, bicalutamide, flutamide and/ornilutamide); an antibody (e.g., Abciximab, Adalimumab, Alemtuzumab,Atlizumab, Basiliximab, Belimumab, Bevacizumab, Brentuximab vedotin,Canakinumab, Cetuximab, Certolizumab pegol, Daclizumab, Denosumab,Eculizumab, Efalizumab, Gemtuzumab, Golimumab, Golimumab, Ibritumomabtiuxetan, Infliximab, Ipilimumab, Muromonab-CD3, Natalizumab,Ofatumumab, Omalizumab, Palivizumab, Panitumumab, Ranibizumab,Rituximab, Tocilizumab, Tositumomab and/or Trastuzumab); ananti-angiogenic agent; a cytokine; a thrombotic agent; a growthinhibitory agent; an anti-helminthic agent; and an immune checkpointinhibitor that targets an immune checkpoint receptor selected fromCTLA-4, PD-1, PD-L1, PD-1-PD-L1, PD-1-PD-L2, T cell immunoglobulin andmucin 3 (TIM3 or HAVCR2), Galectin 9-TIM3, Phosphatidylserine-TIM3,lymphocyte activation gene 3 protein (LAG3), MHC class II-LAG3,4-1BB-4-1BB ligand, OX40-OX40 ligand, GITR, GITR ligand-GITR, CD27,CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40-CD40 ligand,HVEM-LIGHT-LTA, HVEM, HVEM-BTLA, HVEM-CD160, HVEM-LIGHT,HVEM-BTLA-CD160, CD80, CD80-PDL-1, PDL2-CD80, CD244, CD48-CD244, CD244,ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2-TMIGD2,Butyrophilins, including BTNL2, Siglec family, TIGIT and PVR familymembers, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244,CD28, CD86-CD28, CD86-CTLA, CD80-CD28, Phosphatidylserine, TIM3,Phosphatidylserine-TIM3, SIRPA-CD47, VEGF, Neuropilin, CD160, CD30, andCD155 (e.g., CTLA-4 or PD1 or PD-L1) and other immunomodulatory agents,such as interleukin-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL-10,transforming growth factor-β (TGFβ), CD39, CD73 Adenosine-CD39-CD73, andCXCR4-CXCL12.

The subject can have cancer; e.g., the subject has undergone and/or isundergoing and/or will undergo one or more cancer therapies.

Non-limiting examples of cancer include acute myeloid leukemia,adrenocortical carcinoma, Kaposi sarcoma, lymphoma, anal cancer,appendix cancer, teratoid/rhabdoid tumor, basal cell carcinoma, bileduct cancer, bladder cancer, bone cancer, brain cancer, breast cancer,bronchial tumor, carcinoid tumor, cardiac tumor, cervical cancer,chordoma, chronic lymphocytic leukemia, chronic myeloproliferativeneoplasm, colon cancer, colorectal cancer, craniopharyngioma,endometrial cancer, ependymoma, esophageal cancer,esthesioneuroblastoma, Ewing sarcoma, eye cancer, fallopian tube cancer,gallbladder cancer, gastrointestinal carcinoid tumor, gastrointestinalstromal tumor, germ cell tumor, hairy cell leukemia, head and neckcancer, heart cancer, liver cancer, hypopharngeal cancer, pancreaticcancer, kidney cancer, laryngeal cancer, chronic myelogenous leukemia,lip and oral cavity cancer, lung cancer, melanoma, Merkel cellcarcinoma, mesothelioma, mouth cancer, oral cancer, osteosarcoma,ovarian cancer, penile cancer, pharyngeal cancer, prostate cancer,rectal cancer, salivary gland cancer, skin cancer, small intestinecancer, soft tissue sarcoma, testicular cancer, throat cancer, thyroidcancer, urethral cancer, uterine cancer, vaginal cancer, and vulvarcancer.

In other embodiments, the mammal has been identified as having a canceror an infectious disease. Representative infectious diseases include,without limitation, Acinobacter infection, actinomycosis, Africansleeping sickness, acquired immunodeficiency syndrome, amebiasis,anaplasmosis, anthrax, Arcanobacterium haemolyticum infection, Argentinehemorrhagic fever, ascariasis, aspergillosis, astrovirus infection,babesiosis, Bacillus cereus infection, bacterial pneumonia, bacterialvaginosis, Bacteroides infection, balantidiasis, Baylisascarisinfection, BK virus infection, black piedra, Blastocystic hominisinfection, blastomycosis, Bolivian hemorrhagic fever, botulism,Brazilian hemorrhagic fever, brucellosis, bubonic plaque, Burkholderiinfection, Buruli ulcer, Calicivirus infection, camptobacteriosis,candidiasis, cat-scratch disease, cellulitis, Chagas disease, chancroid,chickenpox, chikungunya, chlamydia, Chlamydophila pneumoniae infection,cholera, chromoblastomycosis, clonorchiasis, Clostridium difficileinfection, coccidioidomycosis, Colorado tick fever, common cold,Creutzfeldt-Jakob disease, Crimean-Congo hemorrhagic fever,crytococcosis, cryptosporidiosis, cutaneous larva migrans,cyclosporiasis, cysticercosis, cytomegalovirus infection, dengue fever,Desmodesmus infection, deintamoebiasis, diphtheria, diphyllobothriasis,dracunculiasis, ebola hemorrhagic fever, echinococcosis, ehrlichiosis,enterobiasis, Enterococcus infection, Enterovirus infection, epidemictyphus, erythema infection, exanthema subitum, fasciolopsiasis,fasciolosis, fatal familial insomnia, filariasis, food poisoning byClostridium myonecrosis, free-living amebic infection, Fusobacteriuminfection, gas gangrene, geotrichosis, Gerstmann-Sträussler-Scheinkersyndrome, giardiasis, glanders, gnathostomiasis, gonorrhea, granulomainguinale, Group A streptococcal infection, Group B streptococcalinfection, Haemophilus influenzae infection, hand foot and mouthdisease, hantavirus pulmonary syndrome, Heartland virus disease,Heliobacter pylori infection, hemolytic-uremic syndrome, hemorrhagicfever with renal syndrome, hepatitis A, hepatitis B, hepatitis C,hepatitis D, hepatitis E, herpes simplex, histoplasmosis, hookworminfection, human bocavirus infection, human ewingii ehrlichiosis, humangranulocyte anaplasmosis, human metapneuomovirus infection, humanmonocytic ehrlichiosis, human papillomavirus infection, humanparainfluenza virus infection, hymenolepiasis, Epstein-Barr virusinfectious mononucleosis, influenza, isosporiasis, Kawasaki disease,keratitis, Kingella kingae infection, kuru, lassa fever, Legionnaires'disease, Pontiac fever, leishmaniasis, leprosy, leptospirosis,listeriosis, lyme disease, lymphatic filariasis, lymphocyticchoriomeningitis, malaria, Marburg hemorrhagic fever, measles, MiddleEast respiratory syndrome, melioidosis, meningitis, meningococcaldisease, metagonimiasis, microsporidiosis, molluscum contagiosum,monkeypox, mumps, murine typhus, mycoplasma pneumonia, mycetoma,myiasis, neonatal conjunctivitis, variant Creutzfeldt-Jakob disease,nocardiosis, onchocerciasis, paracoccidioidomycosis, paragonimiasis,pasteurellosis, pediculosis capitis, pediculosis corporis, pediculosispubis, pelvic inflammatory disease, pertussis, plague, pneumonia,poliomyelitis, Prevotella infection, primary amoebicmeningoencephalitis, progressive multifocal leukoencephalopathy,psittacosis, Q fever, rabies, relapsing fever, respiratory syncytialvirus infection, rhinosporidiosis, rhinovirus infection, rickettsialinfection, rickettsialpox, Rift Valley Fever, Rocky Mountain spottedfever, rotavirus infection, rubella, salmonellosis, severe acuterespiratory syndrome, scabies, schistosomiasis, sepsis, shigellosis,shingles, smallpox, sporothrichosis, staphylococcal food poisoning,staphylococcal infection, staphylococcal infection, strongyloidiasis,subacute sclerosing panencephalitis, syphilis, taeniasis, tetanus, tineabarabe, tinea capitis, tinea corporis, tinea cruris, tinea manum, tineanigra, tinea pedis, tinea unguium, tinea versicolor, toxocariasis,trachoma, toxoplasmosis, trichinosis, trichomoniasis, trichuriasis,tuberculosis, tularemia, typhoid fever, Ureaplasma urealyticuminfection, valley fever, Venezuelan hemorrhagic fever, viral pneumonia,West Nile fever, white piedra, Yersinia psuedotuberculosis infection,yersiniosis, yellow fever, and zygomycosis.

The chemical entity can be administered intratumorally.

The chemical entity can be administered systemically (including but notlimited to orally, subcutaneously, intramuscular, intravenously).

The methods can further include identifying the subject.

Other embodiments include those described in the Detailed Descriptionand/or in the claims.

Additional Definitions

To facilitate understanding of the disclosure set forth herein, a numberof additional terms are defined below. Generally, the nomenclature usedherein and the laboratory procedures in organic chemistry, medicinalchemistry, and pharmacology described herein are those well-known andcommonly employed in the art. Unless defined otherwise, all technicaland scientific terms used herein generally have the same meaning ascommonly understood by one of ordinary skill in the art to which thisdisclosure belongs.

As used herein, the term “NLRP3” is meant to include, withoutlimitation, nucleic acids, polynucleotides, oligonucleotides, sense andantisense polynucleotide strands, complementary sequences, peptides,polypeptides, proteins, homologous and/or orthologous NLRP3 molecules,isoforms, precursors, mutants, variants, derivatives, splice variants,alleles, different species, and active fragments thereof.

The term “acceptable” with respect to a formulation, composition oringredient, as used herein, means having no persistent detrimentaleffect on the general health of the subject being treated.

“API” refers to an active pharmaceutical ingredient.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of a chemical entity (e.g., acompound exhibiting activity as a mitochondrial uncoupling agent or apharmaceutically acceptable salt and/or hydrate and/or cocrystalthereof; e.g., a compound, such as niclosamide or a pharmaceuticallyacceptable salt and/or hydrate and/or cocrystal thereof, e.g., acompound, such as a niclosamide analog, or a pharmaceutically acceptablesalt and/or hydrate and/or cocrystal thereof) being administered whichwill relieve to some extent one or more of the symptoms of the diseaseor condition being treated. The result includes reduction and/oralleviation of the signs, symptoms, or causes of a disease, or any otherdesired alteration of a biological system. For example, an “effectiveamount” for therapeutic uses is the amount of the composition comprisinga compound as disclosed herein required to provide a clinicallysignificant decrease in disease symptoms. An appropriate “effective”amount in any individual case is determined using any suitabletechnique, such as a dose escalation study.

The term “excipient” or “pharmaceutically acceptable excipient” means apharmaceutically-acceptable material, composition, or vehicle, such as aliquid or solid filler, diluent, carrier, solvent, or encapsulatingmaterial. In one embodiment, each component is “pharmaceuticallyacceptable” in the sense of being compatible with the other ingredientsof a pharmaceutical formulation, and suitable for use in contact withthe tissue or organ of humans and animals without excessive toxicity,irritation, allergic response, immunogenicity, or other problems orcomplications, commensurate with a reasonable benefit/risk ratio. See,e.g., Remington: The Science and Practice of Pharmacy, 22nd Edition,Pharmaceutical Press, London, U K (2012); Handbook of PharmaceuticalExcipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and theAmerican Pharmaceutical Association: (2009); Handbook of PharmaceuticalAdditives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: (2007);Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRCPress LLC: Boca Raton, Fla., (2009).

The term “pharmaceutically acceptable salt” refers to a formulation of acompound that does not cause significant irritation to an organism towhich it is administered and does not abrogate the biological activityand properties of the compound. In certain instances, pharmaceuticallyacceptable salts are obtained by reacting a compound described herein,with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid,nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid and the like. In some instances,pharmaceutically acceptable salts are obtained by reacting a compoundhaving acidic group described herein with a base to form a salt such asan ammonium salt, an alkali metal salt, such as a sodium or a potassiumsalt, an alkaline earth metal salt, such as a calcium or a magnesiumsalt, a salt of organic bases such as dicyclohexylamine,N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts withamino acids such as arginine, lysine, and the like, or by other methodspreviously determined. The pharmacologically acceptable salt is notspecifically limited as far as it can be used in medicaments. Examplesof a salt that the compounds described hereinform with a base includethe following: salts thereof with inorganic bases such as sodium,potassium, magnesium, calcium, and aluminum; salts thereof with organicbases such as methylamine, ethylamine and ethanolamine; salts thereofwith basic amino acids such as lysine and ornithine; and ammonium salt.The salts may be acid addition salts, which are specifically exemplifiedby acid addition salts with the following: mineral acids such ashydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid,nitric acid, and phosphoric acid:organic acids such as formic acid,acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid,fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid,citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic aminoacids such as aspartic acid and glutamic acid.

The term “pharmaceutical composition” refers to a mixture of a compounddescribed herein with other chemical components (referred tocollectively herein as “excipients”), such as carriers, stabilizers,diluents, dispersing agents, suspending agents, and/or thickeningagents. The pharmaceutical composition facilitates administration of thecompound to an organism. Multiple techniques of administering a compoundexist in the art including, but not limited to: rectal, oral,intravenous, aerosol, parenteral, ophthalmic, pulmonary, and topicaladministration.

The term “subject” refers to an animal, including, but not limited to, aprimate (e.g., human), monkey, cow, pig, sheep, goat, horse, dog, cat,rabbit, rat, or mouse. The terms “subject” and “patient” are usedinterchangeably herein in reference, for example, to a mammaliansubject, such as a human.

The terms “treat,” “treating,” and “treatment,” in the context oftreating a disease or disorder, are meant to include alleviating orabrogating a disorder, disease, or condition, or one or more of thesymptoms associated with the disorder, disease, or condition; or toslowing the progression, spread or worsening of a disease, disorder orcondition or of one or more symptoms thereof. The “treatment of cancer”,refers to one or more of the following effects: (1) inhibition, to someextent, of tumor growth, including, (i) slowing down and (ii) completegrowth arrest; (2) reduction in the number of tumor cells; (3)maintaining tumor size; (4) reduction in tumor size; (5) inhibition,including (i) reduction, (ii) slowing down or (iii) complete prevention,of tumor cell infiltration into peripheral organs; (6) inhibition,including (i) reduction, (ii) slowing down or (iii) complete prevention,of metastasis; (7) enhancement of anti-tumor immune response, which mayresult in (i) maintaining tumor size, (ii) reducing tumor size, (iii)slowing the growth of a tumor, (iv) reducing, slowing or preventinginvasion and/or (8) relief, to some extent, of the severity or number ofone or more symptoms associated with the disorder.

The term “halo” refers to fluoro (F), chloro (Cl), bromo (Br), or iodo(I).

The term “alkyl” refers to a hydrocarbon chain that may be a straightchain or branched chain, containing the indicated number of carbonatoms. For example, C₁₋₁₀ indicates that the group may have from 1 to 10(inclusive) carbon atoms in it. Non-limiting examples include methyl,ethyl, iso-propyl, tert-butyl, n-hexyl.

The term “haloalkyl” refers to an alkyl, in which one or more hydrogenatoms is/are replaced with an independently selected halo.

The term “alkoxy” refers to an —O-alkyl radical (e.g., —OCH₃).

The term “alkylene” refers to a branched or unbranched divalent alkyl(e.g., —CH₂—).

The term “alkenyl” refers to a hydrocarbon chain that may be a straightchain or branched chain having one or more carbon-carbon double bonds.The alkenyl moiety contains the indicated number of carbon atoms. Forexample, C₂₋₆ indicates that the group may have from 2 to 6 (inclusive)carbon atoms in it.

The term “alkynyl” refers to a hydrocarbon chain that may be a straightchain or branched chain having one or more carbon-carbon triple bonds.The alkynyl moiety contains the indicated number of carbon atoms. Forexample, C₂₋₆ indicates that the group may have from 2 to 6 (inclusive)carbon atoms in it.

The term “aryl” refers to a 6-carbon monocyclic, 10-carbon bicyclic, or14-carbon tricyclic aromatic ring system wherein 0, 1, 2, 3, or 4 atomsof each ring may be substituted by a substituent, and wherein the ringcomprising a monocyclic radical is aromatic and wherein at least one ofthe fused rings comprising a bicyclic or tricyclic radical is aromatice.g. tetrahydronaphthyl. Examples of aryl groups also include phenyl,naphthyl and the like.

The term “cycloalkyl” as used herein includes saturated cyclichydrocarbon groups having 3 to 10 carbons, preferably 3 to 8 carbons,and more preferably 3 to 6 carbons, wherein the cycloalkyl group may beoptionally substituted. Preferred cycloalkyl groups include, withoutlimitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. The term“cycloalkylene” as used herein refers to divalent cycloalkyl.

The term “heteroaryl” refers to an aromatic 5-8 membered monocyclic,8-12 membered bicyclic, or 11-14 membered tricyclic ring system having1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S(e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S ifmonocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2, 3,or 4 atoms of each ring may be substituted by a substituent, and whereinthe ring comprising a monocyclic radical is aromatic and wherein atleast one of the fused rings comprising a bicyclic or tricyclic radicalis aromatic (but does not have to be a ring which contains a heteroatom,e.g. tetrahydroisoquinolinyl. Examples of heteroaryl groups also includepyridyl, furyl or furanyl, imidazolyl, benzimidazolyl, pyrimidinyl,thiophenyl or thienyl, quinolinyl, indolyl, thiazolyl, and the like.

The term “heterocyclyl” refers to a nonaromatic 5-8 membered monocyclic,8-12 membered bicyclic, or 11-14 membered tricyclic ring system having1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S(e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S ifmonocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3atoms of each ring may be substituted by a substituent. Examples ofheterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl,morpholinyl, tetrahydrofuranyl, and the like. The term“heterocycloalkylene” refers to divalent heterocyclyl.

In addition, atoms making up the compounds of the present embodimentsare intended to include all isotopic forms of such atoms. Isotopes, asused herein, include those atoms having the same atomic number butdifferent mass numbers. By way of general example and withoutlimitation, isotopes of hydrogen include tritium and deuterium, andisotopes of carbon include ¹³C and ¹⁴C.

The details of one or more embodiments of the invention are set forth inthe accompanying drawings and the description below. Other features andadvantages of the invention will be apparent from the description anddrawings, and from the claims.

DETAILED DESCRIPTION

This disclosure features chemical entities (e.g., a compound or apharmaceutically acceptable salt, and/or hydrate, and/or cocrystal,and/or drug combination of the compound) that modulate (e.g., agonizesor partially agonizes) NLRP3 that are useful, e.g., for treating acondition, disease or disorder in which an increase in NLRP3 signalingmay correct a deficiency in innate immune activity (e.g., a condition,disease or disorder associated with an insufficient immune response)that contributes to the pathology and/or symptoms and/or progression ofthe condition, disease or disorder (e.g., cancer) in a subject (e.g., ahuman). This disclosure also features compositions as well as othermethods of using and making the same.

Formula I Compounds

In one aspect, compounds of Formula I, or a pharmaceutically acceptablesalt thereof are featured:

wherein R¹ and R², are defined according to (1) or (2) below:

(1):

R¹ is independently selected from the group consisting of: H,unsubstituted C₁₋₆ alkyl, CHO, C(═O)R^(a), —C(═O)OR^(a),—S(O)₁₋₂(R^(b)), —S(O)₁₋₂NR^(c)R^(d), and —C(═O)NR^(c)R^(d);

R² is independently selected from the group consisting of: H andunsubstituted C₁₋₆ alkyl;

OR

(2):

R¹ and R², together with the nitrogen atom to which each is attachedforms a saturated or unsaturated ring including from 3-10 ring atoms,wherein the ring includes:

(a) from 1-9 ring carbon atoms, each of which is optionally substitutedwith from 1-2 independently selected R^(f), and

(b) from 0-3 ring heteroatoms (in addition to the nitrogen atom attachedto R¹ and R²), each of which is independently selected from the groupconsisting of N, N(R^(e)), O, and S; and

provided that at least one of the 3-10 ring atoms is —C(O)—;

R³ is:

(i) H;

(ii) unsubstituted C₁₋₂ alkyl;

(iii) X—R⁸, wherein X is an unbranched C₁₋₆ alkylene, and R⁸ is —OH,C₁₋₄ alkoxy, —C₁₋₄ haloalkoxy, CO₂R^(a), —CONR^(c)R^(d), cyano, or—NR^(c′)R^(d′);

(iv) (C₁₋₃ alkylene)-(C₆-C₁₀ aryl), wherein the aryl is optionallysubstituted with from 1-3 substituents independently selected from thegroup consisting of: C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, and C₁₋₄haloalkoxy; or

(v) (C₁₋₃ alkylene)heteroaryl including from 5-6 ring atoms, whereinfrom 1-4 ring atoms are each independently selected from the groupconsisting of N, N(R^(e)), O, and S, and wherein the heteroaryl isoptionally substituted with from 1-3 substituents independently selectedfrom the group consisting of: C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy,and C₁₋₄ haloalkoxy;

R⁴ and R⁵ are each independently selected from the group consisting of:

(i) hydrogen;

(ii) halo;

(iii) cyano;

(iv) —C(═O)OH;

(iv) —C(═O)OR^(a).

(v) —C(═O)NR^(c)R^(d);

(vi) —(C₀₋₃ alkylene)-C₃₋₁₀ cycloalkyl, wherein the cycloalkyl isoptionally substituted with from 1-4 independently selected R^(f);

(vii) —(C₀₋₃ alkylene)-heterocyclyl including from 3-10 ring atoms,wherein from 1-3 ring atoms are each independently selected from thegroup consisting of N(R^(e)), O, and S, wherein the heterocyclyl isoptionally substituted with from 1-4 independently selected R^(f);

(viii) —(C₀₋₃ alkylene)-(C₆-C₁₀ aryl) optionally substituted with from1-4 R^(g);

(ix) —(C₀₋₃ alkylene)-heteroaryl including from 5-10 ring atoms, whereinfrom 1-4 ring atoms are each independently selected from the groupconsisting of N, N(R^(e)), O, and S, wherein the heteroaryl isoptionally substituted with from 1-3 R^(g);

(x) —Y—C₆-C₁₀ aryl optionally substituted with from 1-4 R^(g), wherein Yis O, N(R^(e)), or S;

(xi) —Y-heteroaryl including from 5-10 ring atoms, wherein from 1-4 ringatoms are each independently selected from the group consisting of N,N(R^(e)), O, and S, wherein the heteroaryl is optionally substitutedwith from 1-3 R^(g), wherein Y is O, N(R^(e)), or S;

(xii) —NR_(c′)R^(d′);

(xiii) C₁₋₆ alkyl optionally substituted with from 1-2 independentlyselected R^(h);

(xiv) C₁₋₄ haloalkyl;

(xv) C₁₋₆ alkoxy;

(xvi) C₁₋₄ haloalkoxy;

(xvii) —S(O)₁₋₂(R^(b));

(xviii) —S(O)₁₋₂NR^(c)R^(d);

(xviv) —(C₀₋₃ alkylene)-heterocycloalkenyl including from 3-10 ringatoms, wherein from 1-3 ring atoms are each independently selected fromthe group consisting of N(R^(e)), O, and S, wherein the heterocyclyl isoptionally substituted with from 1-4 independently selected R^(f);

each of R⁶ and R⁷ is independently selected from the group consistingof: H and unsubstituted C₁₋₂ alkyl; or R⁶ and R⁷ together with thecarbon atom to which each is attached, forms a C₃-C₅ cycloalkyl,optionally substituted with from 1-4 independently selected R^(f);

provided that when R¹ and R², are defined according to (1), then each ofR⁶ and R⁷ is H;

provided that when R¹ and R², are defined according to (2), then each ofR⁶ and R⁷ is independently selected from the group consisting of: H andunsubstituted C₁₋₂ alkyl; or R⁶ and R⁷ together with the carbon atom towhich each is attached, forms a C₃-C₅ cycloalkyl, optionally substitutedwith from 1-4 independently selected R^(f);

R^(a) is:

(i) C₁₋₆ alkyl optionally substituted with from 1-2 independentlyselected R^(h).

(ii) —(C₀₋₃ alkylene)-C₃₋₁₀ cycloalkyl, wherein the cycloalkyl isoptionally substituted with from 1-4 independently selected R^(f);

(iii) —(C₁₋₃ alkylene)-heterocyclyl including from 3-10 ring atoms,wherein from 1-3 ring atoms are each independently selected from thegroup consisting of N(R^(e)), O, and S, wherein the heterocyclyl isoptionally substituted with from 1-4 independently selected R^(f);

(iv) —(C₀₋₃ alkylene)-phenyl optionally substituted with from 1-5independently selected R^(g); or

(v) —(C₀₋₃ alkylene)-heteroaryl including from 5-10 ring atoms, whereinfrom 1-4 ring atoms are each independently selected from the groupconsisting of N, N(R^(e)), O, and S, wherein the heteroaryl isoptionally substituted with from 1-3 independently selected R^(g);

R^(b) is: C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy,phenyl optionally substituted with from 1-3 R^(g), or heteroarylincluding from 5-6 ring atoms, wherein from 1-4 ring atoms are eachindependently selected from the group consisting of N, N(R^(e)), O, andS, wherein the heteroaryl is optionally substituted with from 1-3 R^(g);

each occurrence of R^(c) and R^(d) is independently selected from thegroup consisting of: H and C₁₋₄ alkyl; or R^(c) and R^(d) together withthe nitrogen atom to which each is attached forms a ring including from3-8 ring atoms, wherein the ring includes: (a) from 1-7 ring carbonatoms, each of which is optionally substituted with from 1-2independently selected R^(f); and (b) from 0-3 ring heteroatoms (inaddition to the nitrogen atom attached to R^(c) and R^(d)), which areeach independently selected from the group consisting of N(R^(e)), O,and S;

each occurrence of R^(c′) and R^(d′) is independently selected from thegroup consisting of: H, R^(a), —C(═O)R^(a), —C(═O)OR^(a),—S(O)₁₋₂(R^(b)), and —C(═O)NR^(c)R^(d); or R^(c′) and R^(d′) togetherwith the nitrogen atom to which each is attached forms a ring includingfrom 3-8 ring atoms, wherein the ring includes: (a) from 1-7 ring carbonatoms, each of which is optionally substituted with from 1-2independently selected R^(f); and (b) from 0-3 ring heteroatoms (inaddition to the nitrogen atom attached to R^(c′) and R^(d′)), which areeach independently selected from the group consisting of N(R^(e)), O,and S;

each occurrence of R^(e) is independently selected from the groupconsisting of H; C₁₋₄ alkyl; C₃₋₆ cycloalkyl; phenyl; —C(═O)(C₁₋₄alkyl); —C(═O)O(C₁₋₄ alkyl); and —S(O)₁₋₂(C₁₋₄ alkyl); wherein each C₁₋₄alkyl is optionally substituted with from 1-2 independently selectedR^(h); each C₃₋₆ cycloalkyl is optionally substituted with from 1-2independently selected R^(f); and each phenyl is optionally substitutedwith from 1-2 independently selected R^(g);

each occurrence of R^(f) is independently selected from the groupconsisting of: C₁₋₆ alkyl optionally substituted with from 1-2independently selected R^(h); C₁₋₄ haloalkyl; —OH; oxo; —F; —Cl;—N(R′)(R″); —N(R′)(C(═O)C₁₋₄ alkyl); C₁₋₄ alkoxy; C₁₋₄ haloalkoxy;—C(═O)(C₁₋₄ alkyl); —C(═O)O(C₁₋₄ alkyl); —C(═O)OH; —C(═O)N(R′)(R″);—S(O)₁₋₂(C₁₋₄ alkyl); cyano; heteroaryl including from 5-10 ring atoms,wherein from 1-4 ring atoms are each independently selected from thegroup consisting of N, N(R^(e)), O, and S, wherein the heteroaryl isoptionally substituted with from 1-3 R^(g); and phenyl optionallysubstituted with from 1-4 R^(g); and wherein each occurrence of R′ andR″ is independently selected from the group consisting of: H and C₁₋₄alkyl;

each occurrence of R^(g) is independently selected from the groupconsisting of:

(i) halo;

(ii) cyano;

(iii) C₁₋₆ alkyl optionally substituted with from 1-2 independentlyselected R^(h);

(iv) C₂₋₆ alkenyl;

(v) C₂₋₆ alkynyl;

(vi) C₁₋₄ haloalkyl;

(vii) C₁₋₄ alkoxy;

(viii) C₁₋₄ haloalkoxy;

(ix) —(C₀₋₃ alkylene)-C₃₋₆ cycloalkyl optionally substituted with from1-4 independently selected C₁₋₄ alkyl;

(x) —(C₀₋₃ alkylene)-heterocyclyl including from 3-6 ring atoms, whereinfrom 1-3 ring atoms are each independently selected from the groupconsisting of nitrogen, oxygen and sulfur, wherein the heterocyclyl isoptionally substituted with from 1-4 independently selected C₁₋₄ alkyl;

(xi) —S(O)₁₋₂(C₁₋₆ alkyl);

(xii) —NO₂;

(xiii) —OH;

(xiv) —N(R′)(R″);

(xv) —N(R′)(C(═O)C₁₋₃ alkyl);

(xvi) —C(═O)(C₁₋₄ alkyl);

(xvii) —C(═O)O(C₁₋₄ alkyl);

(xviii) —C(═O)OH; and

(xix) —C(═O)N(R′)(R″);

wherein each occurrence of R′ and R″ is independently selected from thegroup consisting of H and C₁₋₄ alkyl; and

each occurrence of R^(h) is independently selected from the groupconsisting of: —OH, —OBn, —F, —N(R′)(R″), —N(R′)(C(═O)C₁₋₄ alkyl),—N(R′)(C(═O)OC₁₋₄ alkyl), C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, —C(═O)O(C₁₋₄alkyl), —C(═O)OH, —C(═O)N(R′)(R″), —S(O)₁₋₂(C₁₋₄ alkyl), and cyano;wherein each occurrence of R′ and R″ is independently selected from thegroup consisting of: H and C₁₋₄ alkyl.

In some embodiments, one or more (e.g., all) of the provisions apply:

with the proviso that when R⁸ is NR^(c′)R^(d′), then R¹ is not—S(O)₁₋₂(R^(b));

with the proviso that when R⁸ is NR^(c′)R^(d′) and R¹ and R², togetherwith the nitrogen atom to which each is attached, forms heterocyclylincluding from 3-10 ring atoms, then none of the ring atoms of theheterocyclyl formed from R¹ and R² are S;

with the proviso that when R⁸ is NR^(c′)R^(d′) and R¹ and R², togetherwith the nitrogen atom to which each is attached, forms heterocyclyl,then the heterocyclyl formed from R¹ and R² does not include 5 ringatoms;

with the proviso that when R⁸ is NR^(c′)R^(d′), then R¹ and R², togetherwith the nitrogen atom to which each is attached does not form

with the proviso that when R⁸ is NR^(c′)R^(d′), then R¹ is not—C(═O)NR^(c)R^(d);

with the proviso that when R⁸ is NR^(c′)R^(d′), R¹ is —C(═O)NR^(c)R^(d),and one of R^(c) and R^(d) is H; then the other of R^(c) and R^(d) isnot selected from H or C₁₋₄ alkyl;

with the proviso that when R⁸ is NR^(c′)R^(d′), R¹ is —C(═O)NR^(c)R^(d),and one of R^(c) and R^(d) is H; then the other of R^(c) and R^(d) isnot selected from H, Me, or Et;

with the proviso that the compound of Formula I is not selected from:

In one aspect, compounds of Formula I, or a pharmaceutically acceptablesalt thereof are featured:

wherein R¹ and R², are defined according to (1) or (2) below:

(1):

R¹ is independently selected from the group consisting of: H,unsubstituted C₁₋₆ alkyl, C(═O)R^(a), —C(═O)OR^(a), —S(O)₁₋₂(R^(b)),—S(O)₁₋₂NR^(c)R^(d), and —C(═O)NR^(c)R^(d);

R² is independently selected from the group consisting of: H andunsubstituted C₁₋₆ alkyl;

OR

(2):

R¹ and R², together with the nitrogen atom to which each is attachedforms a saturated or unsaturated ring including from 3-10 ring atoms,wherein the ring includes:

(a) from 1-9 ring carbon atoms, each of which is optionally substitutedwith from 1-2 independently selected R^(f), and

(b) from 0-3 ring heteroatoms (in addition to the nitrogen atom attachedto R¹ and R²), each of which is independently selected from the groupconsisting of N, N(R^(e)), O, and S; and

provided that at least one of the 3-10 ring atoms is —C(O)—;

R³ is:

(i) H;

(ii) unsubstituted C₁₋₂ alkyl;

(iii) X—R⁸, wherein X is an unbranched C₁₋₆ alkylene, and R⁸ is —OH,C₁₋₄ alkoxy, —C₁₋₄ haloalkoxy, CO₂R^(a), —CONR^(c)R^(d), cyano, or—NR^(c′)R^(d′);

(iv) (C₁₋₃ alkylene)-(C₆-C₁₀ aryl), wherein the aryl is optionallysubstituted with from 1-3 substituents independently selected from thegroup consisting of: C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, and C₁₋₄haloalkoxy; or

(v) (C₁₋₃ alkylene)heteroaryl including from 5-6 ring atoms, whereinfrom 1-4 ring atoms are each independently selected from the groupconsisting of N, N(R^(e)), O, and S, and wherein the heteroaryl isoptionally substituted with from 1-3 substituents independently selectedfrom the group consisting of: C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy,and C₁₋₄ haloalkoxy;

R⁴ and R⁵ are each independently selected from the group consisting of:

(i) hydrogen;

(ii) halo;

(iii) cyano;

(iv) —C(═O)OH;

(iv) —C(═O)OR^(a);

(v) —C(═O)NR^(c)R^(d);

(vi) —(C₀₋₃ alkylene)-C₃₋₁₀ cycloalkyl, wherein the cycloalkyl isoptionally substituted with from 1-4 independently selected R^(f);

(vii) —(C₀₋₃ alkylene)-heterocyclyl including from 3-10 ring atoms,wherein from 1-3 ring atoms are each independently selected from thegroup consisting of N(R^(e)), O, and S, wherein the heterocyclyl isoptionally substituted with from 1-4 independently selected R_(f);

(viii) —(C₀₋₃ alkylene)-(C₆-C₁₀ aryl) optionally substituted with from1-4 R^(g);

(ix) —(C₀₋₃ alkylene)-heteroaryl including from 5-10 ring atoms, whereinfrom 1-4 ring atoms are each independently selected from the groupconsisting of N, N(R^(e)), O, and S, wherein the heteroaryl isoptionally substituted with from 1-3 R^(g);

(x) —Y—C₆-C₁₀ aryl optionally substituted with from 1-4 R^(g), wherein Yis O, N(R^(e)), or S;

(xi) —Y-heteroaryl including from 5-10 ring atoms, wherein from 1-4 ringatoms are each independently selected from the group consisting of N,N(R^(e)), O, and S, wherein the heteroaryl is optionally substitutedwith from 1-3 R^(g), wherein Y is O, N(R^(e)), or S;

(xii) —NR^(c′)R^(d′).

(xiii) C₁₋₆ alkyl optionally substituted with from 1-2 independentlyselected R^(h);

(xiv) C₁₋₄ haloalkyl;

(xv) C₁₋₆ alkoxy;

(xvi) C₁₋₄ haloalkoxy;

(xvii) —S(O)₁₋₂(R^(b));

(xviii) —S(O)₁₋₂NR^(c)R^(d);

(xviv) —(C₀₋₃ alkylene)-heterocycloalkenyl including from 3-10 ringatoms, wherein from 1-3 ring atoms are each independently selected fromthe group consisting of N(R^(e)), O, and S, wherein the heterocyclyl isoptionally substituted with from 1-4 independently selected R^(f);

each of R⁶ and R⁷ is independently selected from the group consistingof: H and unsubstituted C₁₋₂ alkyl; or R⁶ and R⁷ together with thecarbon atom to which each is attached, forms a C₃-C₅ cycloalkyl,optionally substituted with from 1-4 independently selected R^(f);

provided that when R¹ and R², are defined according to (1), then each ofR⁶ and R⁷ is H;

provided that when R¹ and R², are defined according to (2), then each ofR⁶ and R⁷ is independently selected from the group consisting of: H andunsubstituted C₁₋₂ alkyl; or R⁶ and R⁷ together with the carbon atom towhich each is attached, forms a C₃-C₅ cycloalkyl, optionally substitutedwith from 1-4 independently selected R^(f);

R^(a) is:

(i) C₁₋₆ alkyl optionally substituted with from 1-2 independentlyselected R^(h).

(ii) —(C₀₋₃ alkylene)-C₃₋₁₀ cycloalkyl, wherein the cycloalkyl isoptionally substituted with from 1-4 independently selected R^(f);

(iii) —(C₁₋₃ alkylene)-heterocyclyl including from 3-10 ring atoms,wherein from 1-3 ring atoms are each independently selected from thegroup consisting of N(R^(e)), O, and S, wherein the heterocyclyl isoptionally substituted with from 1-4 independently selected R^(f);

(iv) —(C₀₋₃ alkylene)-phenyl optionally substituted with from 1-5independently selected R^(g); or

(v) —(C₀₋₃ alkylene)-heteroaryl including from 5-10 ring atoms, whereinfrom 1-4 ring atoms are each independently selected from the groupconsisting of N, N(R^(e)), O, and S, wherein the heteroaryl isoptionally substituted with from 1-3 independently selected R^(g);

R^(b) is: C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy,phenyl optionally substituted with from 1-3 R^(g), or heteroarylincluding from 5-6 ring atoms, wherein from 1-4 ring atoms are eachindependently selected from the group consisting of N, N(R^(e)), O, andS, wherein the heteroaryl is optionally substituted with from 1-3 R^(g);

each occurrence of R^(c) and R^(d) is independently selected from thegroup consisting of: H and C₁₋₄ alkyl; or R^(c) and R^(d) together withthe nitrogen atom to which each is attached forms a ring including from3-8 ring atoms, wherein the ring includes: (a) from 1-7 ring carbonatoms, each of which is optionally substituted with from 1-2independently selected R^(f); and (b) from 0-3 ring heteroatoms (inaddition to the nitrogen atom attached to R^(c) and R^(d)), which areeach independently selected from the group consisting of N(R^(e)), O,and S;

each occurrence of R^(c′) and R^(d′) is independently selected from thegroup consisting of: H, R^(a), —C(═O)R^(a), —C(═O)OR^(a),—S(O)₁₋₂(R^(b)), and —C(═O)NR^(c)R^(d); or R^(c′) and R^(d′) togetherwith the nitrogen atom to which each is attached forms a ring includingfrom 3-8 ring atoms, wherein the ring includes: (a) from 1-7 ring carbonatoms, each of which is optionally substituted with from 1-2independently selected R^(f); and (b) from 0-3 ring heteroatoms (inaddition to the nitrogen atom attached to R^(c′) and R^(d′)), which areeach independently selected from the group consisting of N(R^(e)), O,and S;

each occurrence of R^(e) is independently selected from the groupconsisting of: H; C₁₋₄ alkyl; C₃₋₆ cycloalkyl; phenyl; —C(═O)(C₁₋₄alkyl); —C(═O)O(C₁₋₄ alkyl); and —S(O)₁₋₂(C₁₋₄ alkyl); wherein each C₁₋₄alkyl is optionally substituted with from 1-2 independently selectedR^(h); each C₃₋₆ cycloalkyl is optionally substituted with from 1-2independently selected R^(f); and each phenyl is optionally substitutedwith from 1-2 independently selected R^(g);

each occurrence of R^(f) is independently selected from the groupconsisting of: C₁₋₆ alkyl optionally substituted with from 1-2independently selected R^(h); C₁₋₄ haloalkyl; —OH; oxo; —F; —Cl;—N(R′)(R″); —N(R′)(C(═O)C₁₋₄ alkyl); C₁₋₄ alkoxy; C₁₋₄ haloalkoxy;—C(═O)(C₁₋₄ alkyl); —C(═O)O(C₁₋₄ alkyl); —C(═O)OH; —C(═O)N(R′)(R″);—S(O)₁₋₂(C₁₋₄ alkyl); cyano; heteroaryl including from 5-10 ring atoms,wherein from 1-4 ring atoms are each independently selected from thegroup consisting of N, N(R^(e)), O, and S, wherein the heteroaryl isoptionally substituted with from 1-3 R^(g); and phenyl optionallysubstituted with from 1-4 R^(g); and wherein each occurrence of R′ andR″ is independently selected from the group consisting of: H and C₁₋₄alkyl;

each occurrence of R^(g) is independently selected from the groupconsisting of:

(i) halo;

(ii) cyano;

(iii) C₁₋₆ alkyl optionally substituted with from 1-2 independentlyselected R^(h);

(iv) C₂₋₆ alkenyl;

(v) C₂₋₆ alkynyl;

(vi) C₁₋₄ haloalkyl;

(vii) C₁₋₄ alkoxy;

(viii) C₁₋₄ haloalkoxy;

(ix) —(C₀₋₃ alkylene)-C₃₋₆ cycloalkyl optionally substituted with from1-4 independently selected C₁₋₄ alkyl;

(x) —(C₀₋₃ alkylene)-heterocyclyl including from 3-6 ring atoms, whereinfrom 1-3 ring atoms are each independently selected from the groupconsisting of nitrogen, oxygen and sulfur, wherein the heterocyclyl isoptionally substituted with from 1-4 independently selected C₁₋₄ alkyl;

(xi) —S(O)₁₋₂(C₁₋₆ alkyl);

(xii) —NO₂;

(xiii) —OH;

(xiv) —N(R′)(R″);

(xv) —N(R′)(C(═O)C₁₋₃ alkyl);

(xvi) —C(═O)(C₁₋₄ alkyl);

(xvii) —C(═O)O(C₁₋₄ alkyl);

(xviii) —C(═O)OH; and

(xix) —C(═O)N(R′)(R″);

wherein each occurrence of R′ and R″ is independently selected from thegroup consisting of: H and C₁₋₄ alkyl; and

each occurrence of R^(h) is independently selected from the groupconsisting of: —OH, —F, —N(R′)(R″), —N(R′)(C(═O)C₁₋₄ alkyl),—N(R′)(C(═O)OC₁₋₄ alkyl), C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, —C(═O)O(C₁₋₄alkyl), —C(═O)OH, —C(═O)N(R′)(R″), —S(O)₁₋₂(C₁₋₄ alkyl), and cyano;wherein each occurrence of R′ and R″ is independently selected from thegroup consisting of: H and C₁₋₄ alkyl.

In some embodiments, one or more (e.g., all) of the provisions apply:

with the proviso that when R⁸ is NR^(c′)R^(d′), then R¹ is not—S(O)₁₋₂(R^(b));

with the proviso that when R⁸ is NR^(c′)R^(d′) and R¹ and R², togetherwith the nitrogen atom to which each is attached, forms heterocyclylincluding from 3-10 ring atoms, then none of the ring atoms of theheterocyclyl formed from R¹ and R² are S;

with the proviso that when R⁸ is NR^(c′)R^(d′) and R¹ and R², togetherwith the nitrogen atom to which each is attached, forms heterocyclyl,then the heterocyclyl formed from R¹ and R² does not include 5 ringatoms;

with the proviso that when R⁸ is NR^(c′)R^(d′), then R¹ and R², togetherwith the nitrogen atom to which each is attached does not form:

with the proviso that when R⁸ is NR^(c′)R^(d′), then R¹ is not—C(═O)NR^(c)R^(d);

with the proviso that when R⁸ is NR^(c′)R^(d′), R¹ is —C(═O)NR^(c)R^(d),and one of R^(c) and R^(d) is H; then the other of R^(c) and R^(d) isnot selected from H or C₁₋₄ alkyl;

with the proviso that when R⁸ is NR^(c′)R^(d′), R¹ is —C(═O)NR^(c)R^(d),and one of R^(c) and R^(d) is H; then the other of R^(c) and R^(d) isnot selected from H, Me, or Et;

with the proviso that the compound of Formula I is not selected from:

In some embodiments, R³ is H.

In some embodiments, R³ is unsubstituted C₁₋₂ alkyl (e.g., CH₃).

In some embodiments, one of R⁴ and R⁵ is other than hydrogen.

In some embodiments, R¹ and R² are defined according to (1).

In some embodiments, R¹ and R² are defined according to (2).

In some embodiments, R⁴ and R⁵ further include C₅-C₇ cycloalkenyl and/orazido.

In some embodiments, it is provided that R³ is hydrogen and/or one of R⁴and R⁵ is other than hydrogen.

In some embodiments, each of R⁶ and R⁷ is H.

In some embodiments, R⁸ is —OH, C₁₋₄ alkoxy, —C₁₋₄ haloalkoxy, CO₂R^(a),—CONR^(c)R^(d), and cyano.

Variables R¹, R², R⁶, and R⁷

In some embodiments, R¹, R², R⁶, and R⁷ are defined according to (1)below:

(1):

R¹ is independently selected from the group consisting of: H,unsubstituted C₁₋₆ alkyl, C(═O)R^(a), —C(═O)OR^(a), —S(O)₁₋₂(R^(b)),—S(O)₁₋₂NR^(c)R^(d); and —C(═O)NR^(c)R^(d);

R² is independently selected from the group consisting of: H andunsubstituted C₁₋₆ alkyl.

In these embodiments, each of R⁶ and R⁷ is H.

Variable R¹

In some embodiments, R¹ is independently selected from the groupconsisting of: C(═O)R^(a), —C(═O)OR^(a), —S(O)₁₋₂(R^(b)), and—C(═O)NR^(c)R^(d).

In certain embodiments, R¹ is —C(═O)R^(a).

In certain embodiments, R^(a) is C₁₋₆ alkyl optionally substituted withfrom 1-2 independently selected R^(h). In certain embodiments, R^(a) isunsubstituted C₁₋₆ alkyl. For example, R^(a) can be selected from thegroup consisting of CH₃, CH₂CH₃, and unsubstituted, unbranched C₃₋₆alkyl (e.g., CH₃ or CH₂CH₃). As another example, R^(a) can beunsubstituted, branched C₃₋₆ alkyl (e.g., iso-propyl).

In other embodiments, R^(a) is —(C₀₋₃ alkylene)-C₃₋₁₀ cycloalkyl,wherein the cycloalkyl is optionally substituted with from 1-4independently selected R^(f). For example, R^(a) can be C₃₋₁₀ (e.g.,C₃₋₈ or C₃₋₆) cycloalkyl, wherein the cycloalkyl is optionallysubstituted with from 1-4 independently selected R^(f); e.g., R^(a) canbe unsubstituted C₃₋₁₀ (e.g., C₃₋₈ or C₃₋₆ or C₃₋₅ or C₃₋₄) cycloalkyl.In each of the foregoing embodiments, the cycloalkyl is cyclopropyl.

In other embodiments, R^(a) is —(C₀₋₃ alkylene)-heteroaryl includingfrom 3-10 ring atoms, wherein from 1-3 ring atoms are each independentlyselected from the group consisting of N, N(R^(e)), O, and S, wherein theheteroaryl is optionally substituted with from 1-3 independentlyselected R⁹. For example, R^(a) can be heteroaryl including from 5-10ring atoms, wherein from 1-3 ring atoms are each independently selectedfrom the group consisting of N, N(R^(e)), O, and S, wherein theheteroaryl is optionally substituted with from 1-3 independentlyselected R^(g).

In other embodiments, R^(a) is heteroaryl including from 3-10 ringatoms, wherein from 1-3 ring atoms are each independently selected fromthe group consisting of N, N(R^(e)), O, and S, wherein the heteroaryl isoptionally substituted with from 1-3 independently selected R⁹.

In certain embodiments, R¹ is —S(O)₁₋₂(R^(b)). In certain of theseembodiments, R^(b) is C₁₋₆ alkyl (e.g., CH₃).

In certain embodiments, R¹ is —C(═O)NR^(c)R^(d). In certain of theseembodiments, each of R^(c) and R^(d) is independently selected from thegroup consisting of H and C₁₋₄ alkyl.

In some embodiments, R¹ is unsubstituted C₁₋₆ alkyl. For example, R¹ canbe selected from the group consisting of CH₃, CH₂CH₃, and unsubstituted,unbranched C₃₋₆ alkyl (e.g., R¹ can be CH₃ or CH₂CH₃).

In some embodiments, R¹ is H.

Variable R²

In some embodiments, R² is unsubstituted C₁₋₆ alkyl. For example, R² canbe selected from the group consisting of CH₃, CH₂CH₃, and unsubstituted,unbranched C₃₋₆ alkyl (e.g., R² can be CH₃ or CH₂CH₃).

In some embodiments, R² is H.

Non-Limiting Combinations

In some embodiments, R¹ is independently selected from the groupconsisting of —C(═O)R^(a), —C(═O)OR^(a), —S(O)₁₋₂(R^(b)), and—C(═O)NR^(c)R^(d) (as defined anywhere herein); and R² is unsubstitutedCi-s alkyl (as defined anywhere herein).

In some embodiments, R¹ is independently selected from the groupconsisting of —C(═O)R^(a), —C(═O)OR^(a), —S(O)₁₋₂(R^(b)), and—C(═O)NR^(c)R^(d) (as defined anywhere herein); and R² is H.

In some embodiments, R¹ is unsubstituted C₁₋₆ alkyl (as defined anywhereherein); and R² is unsubstituted C₁₋₆ alkyl (as defined anywhereherein).

In some embodiments, R¹ is unsubstituted C₁₋₆ alkyl (as defined anywhereherein); and R² is H.

In some embodiments, R¹ is H; and R² is H.

In some embodiments, R¹, R², R⁶, and R⁷ are defined according to (2)below:

(2):

R¹ and R², together with the nitrogen atom to which each is attachedforms a saturated or unsaturated (e.g., 1 double bond or 2 double bonds)ring including from 3-10 ring atoms, wherein the ring includes:

(a) from 1-9 ring carbon atoms, each of which is optionally substitutedwith from 1-2 independently selected R^(f), and

(b) from 0-3 ring heteroatoms (in addition to the nitrogen atom attachedto R¹ and R²), each of which is independently selected from the groupconsisting of N, N(R^(e)), O, and S; and

provided that at least one of the 3-10 ring atoms is —C(O)—.

In some embodiments:

R¹ and R², together with the nitrogen atom to which each is attachedforms a saturated ring including from 3-10 ring atoms, wherein the ringincludes:

(a) from 1-9 ring carbon atoms, each of which is optionally substitutedwith from 1-2 independently selected R^(f), and

(b) from 0-3 ring heteroatoms (in addition to the nitrogen atom attachedto R¹ and R²), each of which is independently selected from the groupconsisting of N, N(R^(e)), O, and S; and

provided that at least one of the 3-10 ring atoms is —C(O)—.

In some embodiments:

R¹ and R², together with the nitrogen atom to which each is attachedforms a saturated or unsaturated (e.g., saturated) ring including from4-7 (e.g., 5-6) ring atoms, wherein the ring includes:

(a) from 1-6 (e.g., 1-5) ring carbon atoms, each of which is optionallysubstituted with from 1-2 independently selected R¹, and

(b) from 0-2 ring heteroatoms, each of which is independently selectedfrom the group consisting of N, N(R^(e)), O, and S; and

provided that one ring atom is —C(O)—.

In some embodiments, —C(R⁶)(R⁷)—NR¹R² in formula (I) has the followingformula:

In certain embodiments, —C(R⁶)(R⁷)—NR¹R² in formula (I) has thefollowing formula:

In some embodiments, each of R⁶ and R⁷ is independently selected fromthe group consisting of: H and unsubstituted C₁₋₂ alkyl; or R⁶ and R⁷together with the carbon atom to which each is attached, forms a C₃-C₅cycloalkyl, optionally substituted with from 1-4 independently selectedR^(f).

In certain embodiments, each of R⁶ and R⁷ is H.

In certain embodiments, —C(R⁶)(R⁷)—NR¹R² in formula (I) has thefollowing formula:

wherein:

A₁ is a bond, C(O), CH₂, CHR^(f), or C(R^(f))₂;

A₂ is C(O), CH₂, CHR^(f), or C(R^(f))₂;

A₃ is C(O), CH₂, CHR^(f), or C(R^(f))₂; O, or N(R^(e));

A₄ is CH₂, CHR^(f), or C(R^(f))₂; O, or N(R^(e)); provided that both A₃and A₃ cannot both be N(R^(e)), O or a combination thereof.

In certain embodiments, —C(R⁶)(R⁷)—NR¹R² in formula (I) has thefollowing formula:

wherein:

A₁ is a bond, C(O), CH₂, CHR^(f), or C(R^(f))₂;

A₂ is C(O), CH₂, CHR^(f), or C(R^(f))₂;

A₃ is C(O), CH₂, CHR^(f), or C(R^(f))₂; or N(R^(e));

A₄ is CH₂, CHR^(f), or C(R^(f))₂; or N(R^(e)); provided that both A₃ andA₃ cannot both be N(R^(e)).

In some embodiments, each of R⁶ and R⁷ is independently selected fromthe group consisting of: H and unsubstituted C₁₋₂ alkyl; or R⁶ and R⁷together with the carbon atom to which each is attached, forms a C₃-C₅cycloalkyl, optionally substituted with from 1-4 independently selectedR^(f).

In certain embodiments, each of R⁶ and R⁷ is H.

In some embodiments, A₁ can be a bond (i.e., forming a 5-membered ring).

In certain of these embodiments, each of A₂ and A₄ can be independentlyselected from CH₂, CHR^(f), and C(R^(f))₂. For example, each of A₂ andA₄ can be CH₂. In certain of these embodiments, A₃ is CH₂ or CHR^(f).

In other of these embodiments, one of A₂ and A₄ (e.g., A₂) can be C(O),and the other of A₂ and A₄ (e.g., A₄) can be independently selected fromCH₂, CHR^(f), and C(R^(f))₂. For example, A₂ can be C(O), and A₄ can beCH₂. In certain of these embodiments, A₃ is CH₂ or CHR^(f).

In still other of these embodiments, A₄ can be O or N(R^(e)); and eachof A₂ and A₃ can be independently selected from CH₂, CHR^(f), andC(R^(f))₂ (e.g., one of A₂ and A₃ is CH₂, and the other is CHR^(f) orC(R^(f))₂.

In some embodiments, A₁ is C(O), CH₂, CHR^(f), or C(R^(f))₂ (i.e.,forming a 6-membered ring). In certain of these embodiments, A₂ and A₄can be independently selected from CH₂, CHR^(f), and C(R^(f))₂.

In certain of these embodiments, A₃ is CH₂ or CHR^(f); or A₃ is O, orN(R_(e)).

In certain of the foregoing embodiments, R^(f) is, —OH, C₁₋₄ alkoxy,C₁₋₄ haloalkoxy, -heteroaryl including from 5-10 ring atoms, whereinfrom 1-3 ring atoms are each independently selected from the groupconsisting of N, N(R^(e)), O, and S, wherein the heteroaryl isoptionally substituted with from 1-3 R^(g); and phenyl optionallysubstituted with from 1-4 R^(g).

In some embodiments of (2), each of R⁶ and R⁷ is H.

Variable R³

In some embodiments, R³ is H.

In some embodiments, R³ is unsubstituted C₁₋₂ alkyl (e.g., CH₃).

In some embodiments, R³ is X—R⁸, wherein X is an unbranched C₁₋₆alkylene, and R⁸ is —OH, C₁₋₄ alkoxy, —C₁₋₄ haloalkoxy, CO₂R^(a);—CONR^(c)R^(d), cyano, or —NR^(c′)R^(d′). In certain embodiments, R⁸ is—OH, C₁₋₄ alkoxy, —C₁₋₄ haloalkoxy, CO₂R^(a); —CONR^(c)R^(d), and cyano.

In some embodiments, R³ is —(C₁₋₃ alkylene)-(C₆-C₁₀ aryl), wherein thearyl is optionally substituted with from 1-3 substituents independentlyselected from the group consisting of: C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, and C₁₋₄ haloalkoxy.

In some embodiments, R³ is —(C₁₋₃ alkylene)heteroaryl including from 5-6ring atoms, wherein from 1-3 ring atoms are each independently selectedfrom the group consisting of N, N(R^(e)), O, and S, and wherein theheteroaryl is optionally substituted with from 1-3 substituentsindependently selected from the group consisting of: C₁₋₆ alkyl, C₁₋₄haloalkyl, C₁₋₄ alkoxy, and C₁₋₄ haloalkoxy.

Variables R⁴ and R⁵

In some embodiments, each of R⁴ and R⁵ is hydrogen.

In some embodiments, one of R⁴ and R⁵ is hydrogen (e.g., R⁴), and theother is a substituent other than hydrogen (e.g., R⁵).

In some embodiments, R⁴ and R⁵ are each independently selected from thegroup consisting of:

(i) hydrogen;

(ii) halo;

(iii) cyano;

(vi) —(C₀₋₃ alkylene)-C₃₋₁₀ cycloalkyl, wherein the cycloalkyl isoptionally substituted with from 1-4 independently selected R^(f);

(vii) —(C₀₋₃ alkylene)-heterocyclyl including from 3-10 ring atoms,wherein from 1-3 ring atoms are each independently selected from thegroup consisting of N(R^(e)), O, and S, wherein the heterocyclyl isoptionally substituted with from 1-4 independently selected R^(f);

(viii) —(C₀₋₃ alkylene)-C₆₋₁₀ aryl optionally substituted with from 1-4R^(g);

(ix) —(C₀₋₃ alkylene)-heteroaryl including from 5-10 ring atoms, whereinfrom 1-3 ring atoms are each independently selected from the groupconsisting of N, N(R^(e)), O, and S, wherein the heteroaryl isoptionally substituted with from 1-3 R^(g); and

(xiv) C₁₋₄ haloalkyl.

In some embodiments, one of R⁴ and R⁵ (e.g., R⁵) is:

(ii) halo;

(iii) cyano;

(vi) —(C₀₋₃ alkylene)-C₃₋₁₀ cycloalkyl, wherein the cycloalkyl isoptionally substituted with from 1-4 independently selected R^(f);

(vii) —(C₀₋₃ alkylene)-heterocyclyl including from 3-10 ring atoms,wherein from 1-3 ring atoms are each independently selected from thegroup consisting of N(R^(e)), O, and S, wherein the heterocyclyl isoptionally substituted with from 1-4 independently selected R^(f);

(viii) —(C₀₋₃ alkylene)-C₆₋₁₀ aryl optionally substituted with from 1-4R^(g);

(ix) —(C₀₋₃ alkylene)-heteroaryl including from 5-10 ring atoms, whereinfrom 1-4 ring atoms are each independently selected from the groupconsisting of N, N(R^(e)), O, and S, wherein the heteroaryl isoptionally substituted with from 1-3 R^(g); and

(xiv) C₁₋₄ haloalkyl;

and the other (e.g., R⁴) is H.

In some embodiments, one of R⁴ and R⁵ (e.g., R⁵) is —(C₀₋₃alkylene)-heteroaryl including from 5-10 ring atoms, wherein from 1-4ring atoms are each independently selected from the group consisting ofN, N(R^(e)), O, and S, wherein the heteroaryl is optionally substitutedwith from 1-3 R^(g); and the other (e.g., R⁴) is H.

In certain embodiments, one of R⁴ and R⁵ (e.g., R⁵) is heteroarylincluding from 5-10 ring atoms, wherein from 1-4 ring atoms are eachindependently selected from the group consisting of N, N(R^(e)), O, andS, wherein the heteroaryl is optionally substituted with from 1-3 R^(g);and the other (e.g., R⁴) is H.

Representative heteroaryl groups include, without limitation, thienyl,pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl,triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl,pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl,benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl,cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl,naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl,pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl,thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl,pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine,pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromane,2,3-dihydrobenzo[b][1,4]dioxine, benzo[d][1,3]dioxole,2,3-dihydrobenzofuran, tetrahydroquinoline,2,3-dihydrobenzo[b][1,4]oxathiine, isoindoline,

In certain embodiments, one of R⁴ and R⁵ (e.g., R⁵) is heteroarylincluding from 5-6 ring atoms, wherein from 1-4 ring atoms are eachindependently selected from the group consisting of N, N(R^(e)), O, andS, wherein the heteroaryl is optionally substituted with from 1-2 R^(g);and the other (e.g., R⁴) is H.

In certain embodiments, one of R⁴ and R⁵ (e.g., R⁵) is heteroarylincluding from 5-6 ring atoms, wherein from 1-4 ring atoms are eachindependently selected from the group consisting of N and N(R^(e)),wherein the heteroaryl is optionally substituted with from 1-2 R^(g);and the other (e.g., R⁴) is H.

In certain embodiments, one of R⁴ and R⁵ (e.g., R⁵) is pyrrolyl(C-linked pyrolyl or N-linked pyrolyl), imidazolyl, pyrazolyl,triazolyl, tetrazolyl, pyridyl, pyrimidinyl, or pyrazinyl, wherein eachis optionally substituted with from 1-2 R^(g); and the other (e.g., R⁴)is H.

In certain embodiments, one of R⁴ and R⁵ (e.g., R⁵) is pyrrolyl(C-linked pyrolyl or N-linked pyrolyl), imidazolyl, pyrazolyl,triazolyl, or tetrazolyl, wherein each is optionally substituted withfrom 1-2 R^(g); and the other (e.g., R⁴) is H.

In certain embodiments, one of R⁴ and R⁵ (e.g., R⁵) isN-linked-pyrazolyl, N-linked pyrrolyl, N-linked imidazolyl, N-linkedtriazolyl, or N-linked tetrazolyl, optionally substituted with from 1-2R^(g); and the other (e.g., R⁴) is H.

In certain embodiments, one of R⁴ and R⁵ (e.g., R⁵) isC-linked-pyrazolyl, C-linked pyrrolyl, C-linked imidazolyl, C-linkedtriazolyl, or C-linked tetrazolyl, optionally substituted with from 1-2R^(g); and the other (e.g., R⁴) is H.

In certain embodiments, one of R⁴ and R⁵ (e.g., R⁵) is pyrazolyl,optionally substituted with from 1-2 R^(g); and the other (e.g., R⁴) isH.

In certain embodiments, one of R⁴ and R⁵ (e.g., R⁵) is C-linkedpyrazolyl, optionally substituted with from 1-2 R^(g); and the other(e.g., R⁴) is H.

In certain embodiments, one of R⁴ and R⁵ (e.g., R⁵) is N-linkedpyrazolyl, optionally substituted with from 1-2 R^(g); and the other(e.g., R⁴) is H.

In some embodiments, one of R⁴ and R⁵ (e.g., R⁵) is —(C₀₋₃alkylene)-C₆₋₁₀ aryl, wherein the aryl is optionally substituted withfrom 1-3 R^(g); and the other (e.g., R⁴) is H.

In certain embodiments, one of R⁴ and R⁵ (e.g., R⁵) is C₆₋₁₀ aryl (e.g.,phenyl), optionally substituted with from 1-3 R^(g); and the other(e.g., R⁴) is H.

In some embodiments, one of R⁴ and R⁵ (e.g., R⁵) is —(C₀₋₃alkylene)-heterocyclyl including from 3-10 ring atoms, wherein from 1-3ring atoms are each independently selected from the group consisting ofN(R^(e)), O, and S, wherein the heterocyclyl is optionally substitutedwith from 1-4 independently selected R^(f); and the other (e.g., R⁴) isH.

In some embodiments, one of R⁴ and R⁵ (e.g., R⁵) is heterocyclylincluding from 3-10 ring atoms, wherein from 1-3 ring atoms are eachindependently selected from the group consisting of N(R^(e)), O, and S,wherein the heterocyclyl is optionally substituted with from 1-4independently selected R^(f) (e.g., oxo), and the other (e.g., R⁴) is H.

Non-Limiting Combinations

[1] In some embodiments:

R¹ is independently selected from the group consisting of —C(═O)R^(a),—C(═O)OR^(a), —S(O)₁₋₂(R^(b)), and —C(═O)NR^(c)R^(d);

R² is selected from the group consisting of H, CH₃, CH₂CH₃, andunsubstituted, unbranched C₃₋₆ alkyl;

R³ is:

(i) H; or

(ii) unsubstituted C₁₋₂ alkyl; and

one of R⁴ and R⁵ (e.g., R⁵) is:

(ii) halo;

(iii) cyano;

(vi) —(C₀₋₃ alkylene)-C₃₋₁₀ cycloalkyl, wherein the cycloalkyl isoptionally substituted with from 1-4 independently selected R^(f);

(vii) —(C₀₋₃ alkylene)-heterocyclyl including from 3-10 ring atoms,wherein from 1-3 ring atoms are each independently selected from thegroup consisting of N(R^(e)), O, and S, wherein the heterocyclyl isoptionally substituted with from 1-4 independently selected R^(f);

(viii) —(C₀₋₃ alkylene)-phenyl optionally substituted with from 1-4R^(g);

(ix) —(C₀₋₃ alkylene)-heteroaryl including from 5-10 ring atoms, whereinfrom 1-4 ring atoms are each independently selected from the groupconsisting of N, N(R^(e)), O, and S, wherein the heteroaryl isoptionally substituted with from 1-3 R^(g); and

(xiv) C₁₋₄ haloalkyl; and the other (e.g., R⁴) is H.

[2] In some embodiments:

R¹ is independently selected from the group consisting of H, CH₃,CH₂CH₃, and unsubstituted, unbranched C₃₋₆ alkyl;

R² is selected from the group consisting of H, CH₃, CH₂CH₃, andunsubstituted, unbranched C₃₋₆ alkyl;

R³ is:

(i) H; or

(ii) unsubstituted C₁₋₂ alkyl; and

one of R⁴ and R⁵ (e.g., R⁴) is:

(ii) halo;

(iii) cyano;

(vi) —(C₀₋₃ alkylene)-C₃₋₁₀ cycloalkyl, wherein the cycloalkyl isoptionally substituted with from 1-4 independently selected R^(f);

(vii) —(C₀₋₃ alkylene)-heterocyclyl including from 3-10 ring atoms,wherein from 1-3 ring atoms are each independently selected from thegroup consisting of N(R^(e)), O, and S, wherein the heterocyclyl isoptionally substituted with from 1-4 independently selected R^(f);

(viii) —(C₀₋₃ alkylene)-phenyl optionally substituted with from 1-4R^(g);

(ix) —(C₀₋₃ alkylene)-heteroaryl including from 5-10 ring atoms, whereinfrom 1-4 ring atoms are each independently selected from the groupconsisting of N, N(R^(e)), O, and S, wherein the heteroaryl isoptionally substituted with from 1-3 R^(g); and

(xiv) C₁₋₄ haloalkyl;

and the other (e.g., R⁴) is H.

[3] In some embodiments:

R¹ and R², together with the nitrogen atom to which each is attachedforms a saturated or unsaturated ring including from 3-10 ring atoms,wherein the ring includes:

(a) from 1-9 ring carbon atoms, each of which is optionally substitutedwith from 1-2 independently selected R^(f), and

(b) from 0-3 ring heteroatoms (in addition to the nitrogen atom attachedto R¹ and R²), each of which is independently selected from the groupconsisting of N, N(R^(e)), O, and S; and

provided that one ring atom is —C(O)—;

R³ is:

(i) H; or

(ii) unsubstituted C₁₋₂ alkyl; and

one of R⁴ and R⁵ (e.g., R⁵) is:

(ii) halo;

(iii) cyano;

(vi) —(C₀₋₃ alkylene)-C₃₋₁₀ cycloalkyl, wherein the cycloalkyl isoptionally substituted with from 1-4 independently selected R^(f);

(vii) —(C₀₋₃ alkylene)-heterocyclyl including from 3-10 ring atoms,wherein from 1-3 ring atoms are each independently selected from thegroup consisting of N(R^(e)), O, and S, wherein the heterocyclyl isoptionally substituted with from 1-4 independently selected R^(f);

(viii) —(C₀₋₃ alkylene)-phenyl optionally substituted with from 1-4R^(g);

(ix) —(C₀₋₃ alkylene)-heteroaryl including from 5-10 ring atoms, whereinfrom 1-4 ring atoms are each independently selected from the groupconsisting of N, N(R^(e)), O, and S, wherein the heteroaryl isoptionally substituted with from 1-3 R^(g); and

(xiv) C₁₋₄ haloalkyl;

and the other (e.g., R⁴) is H.

Embodiments of combinations [1]-[3] can include any one or more of thefeatures delineated in the Detailed Descriptions and/or claims.

In some embodiments, R¹ is independently selected from the groupconsisting of —C(═O)R^(a), —C(═O)OR^(a), —S(O)₁₋₂(R^(b)), and—C(═O)NR^(c)R^(d) (as defined anywhere herein); and R² is unsubstitutedC₁₋₆ alkyl (as defined anywhere herein; e.g., CH₃, CH₂CH₃, andunsubstituted, unbranched C₃₋₆ alkyl; e.g., CH₃, CH₂CH₃); or

R¹ is independently selected from the group consisting of: —C(═O)R^(a),—C(═O)OR^(a), —S(O)₁₋₂(R^(b)), and —C(═O)NR^(c)R^(d) (as definedanywhere herein); and R² is H; or

R¹ is unsubstituted C₁₋₆ alkyl (as defined anywhere herein); and R² isunsubstituted C₁₋₆ alkyl ((as defined anywhere herein; e.g., CH₃,CH₂CH₃, and unsubstituted, unbranched C₃₋₆ alkyl; e.g., CH₃, CH₂CH₃); or

R¹ is unsubstituted C₁₋₆ alkyl ((as defined anywhere herein; e.g., CH₃,CH₂CH₃, and unsubstituted, unbranched C₃₋₆ alkyl; e.g., CH₃, CH₂CH₃));and R² is H; or

R¹ is H; and R² is H.

In some embodiments, R¹ is —C(═O)R^(a) (e.g., R^(a) is C₁₋₆ alkyloptionally substituted with from 1-2 independently selected R^(h) e.g.,R^(a) is unsubstituted C₁₋₆ alkyl; e.g., R^(a) is selected from thegroup consisting of CH₃, CH₂CH₃, and unsubstituted, unbranched C₃₋₆alkyl; e.g., R^(a) is CH₃ or CH₂CH₃).

In some embodiments, —C(R⁶)(R⁷)—NR¹R² in formula (I) has formula (A) or(B) as defined anywhere herein.

In some embodiments, wherein R³ is H; or R³ is unsubstituted C₁₋₂ alkyl(e.g., CH₃).

In some embodiments, the compound is selected from the compoundsdelineated in Table 1.

In another aspect, the invention provides a compound of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is independently unsubstituted C₁₋₆ alkyl, C(═O)R^(a), —C(═O)OR^(a),—S(O)₁₋₂(R^(b)), —S(O)₁₋₂NR^(c)R^(d), or —C(═O)NR^(c)R^(d);

R² is independently H or unsubstituted C₁₋₆ alkyl;

R³ is:

(i) H;

(ii) unsubstituted C₁₋₂ alkyl;

(iii) X—R⁸, wherein X is an unbranched C₁₋₆ alkylene, and R⁸ is —OH,C₁₋₄ alkoxy, —C₁₋₄ haloalkoxy, CO₂R^(a), or —CONR^(c)R^(d);

(iv) (C₁₋₃ alkylene)-(C₆-C₁₀ aryl), wherein the aryl is optionallysubstituted with from 1-3 substituents independently selected from C₁₋₆alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, and C₁₋₄ haloalkoxy; or

(v) (C₁₋₃ alkylene)heteroaryl including from 5 to 6 ring atoms, whereinfrom 1 to 4 ring atoms are each independently selected from N, N(R^(e)),O, and S, and wherein the heteroaryl is optionally substituted with from1 to 3 substituents independently selected from C₁₋₆ alkyl, C₁₋₄haloalkyl, C₁₋₄ alkoxy, and C₁₋₄ haloalkoxy;

R⁴ and R⁵ are each independently selected from:

(i) H;

(ii) halo;

(iii) —(C₀₋₃ alkylene)-C₃₋₁₀ cycloalkyl, wherein the cycloalkyl isoptionally substituted with from 1 to 4 independently selected R^(f);

(iv) —(C₀₋₃ alkylene)-heterocyclyl including from 3 to 10 ring atoms,wherein from 1 to 3 ring atoms are each independently selected from:N(R^(e)), O, and S, wherein the heterocyclyl is optionally substitutedwith from 1 to 4 R^(f);

(v) —(C₀₋₃ alkylene)-(C₆-C₁₀ aryl) optionally substituted with from 1 to4 R^(g);

(vi) —(C₀₋₃ alkylene)-heteroaryl including from 5 to 10 ring atoms,wherein from 1 to 4 ring atoms are each independently selected from: N,NHO, and S, wherein the heteroaryl is optionally substituted with from 1to 3 R^(g);

(vii) C₁₋₆ alkyl optionally substituted with from 1-2 independentlyselected R^(h); and

(viii) —(C₀₋₃ alkylene)-C₄₋₁₀ cycloalkenyl, wherein the cycloalkenyl isoptionally substituted with from 1 to 2 R^(f);

R^(a) is:

(i) C₁₋₆ alkyl optionally substituted with from 1 to 2 R^(h);

(ii) —(C₀₋₃ alkylene)-C₃₋₁₀ cycloalkyl, wherein the cycloalkyl isoptionally substituted with from 1 to 2 R^(f);

(iii) —(C₁₋₃ alkylene)-heterocyclyl including from 3 to 10 ring atoms,wherein from 1 to 3 ring atoms are each independently selected fromN(R^(e)), O, and S, wherein the heterocyclyl is optionally substitutedwith from 1 to 4 independently selected R^(f);

(iv) —(C₀₋₃ alkylene)-phenyl optionally substituted with from 1 to 4independently selected R^(g); or

(v) —(C₀₋₃ alkylene)-heteroaryl including from 5 to 10 ring atoms,wherein from 1 to 4 ring atoms are each independently selected from N,N(R^(e)), O, and S, wherein the heteroaryl is optionally substitutedwith from 1 to 3 independently selected R^(g);

R^(b) is C₁₋₆ alkyl;

each occurrence of R^(c) and R^(d) is independently H or C₁₋₄ alkyl;

each occurrence of R^(e) is independently H or C₁₋₄ alkyl;

each occurrence of R^(f) is independently C₁₋₆ alkyl, C₁₋₄ haloalkyl,—OH, F, Cl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, cyano, or phenyl optionallysubstituted with from 1 to 4 R^(g);

each occurrence of R^(g) is independently halo, cyano, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₁₋₄ alkoxy, or C₁₋₄ haloalkoxy; and

each occurrence of R^(h) is independently —OH, F, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, or cyano.

In another aspect, the invention provides a compound of Formula (II) ora pharmaceutically acceptable salt thereof, wherein:

R³ is H, unsubstituted C₁₋₂ alkyl, or X—R⁸, wherein X is an unbranchedC₂₋₆ alkylene, and R⁸ is CO₂R^(a), or —CONR^(c)R^(d);

R⁴ is independently H or halo;

R⁵ is independently selected from:

(i) H;

(ii) halo;

(iii) —(C₀₋₃ alkylene)-C₃₋₁₀ cycloalkyl, wherein the cycloalkyl isoptionally substituted with from 1 to 4 independently selected R^(f);

(iv) —(C₀₋₃ alkylene)-heterocyclyl including from 3 to 10 ring atoms,wherein from 1 to 3 ring atoms are each independently selected from:N(R^(e)), O, and S, wherein the heterocyclyl is optionally substitutedwith from 1 to 4 R^(f);

(v) —(C₀₋₃ alkylene)-(C₆-C₁₀ aryl) optionally substituted with from 1 to4 R^(g);

(v) —(C₀₋₃ alkylene)-heteroaryl including from 5 to 10 ring atoms,wherein from 1 to 4 ring atoms are each independently selected from: N,NH, O, and S, wherein the heteroaryl is optionally substituted with from1 to 3 R^(g);

(vi) C₁₋₆ alkyl optionally substituted with from 1-2 independentlyselected R^(h); and

(vii) —(C₀₋₃ alkylene)-C₄₋₁₀ cycloalkenyl, wherein the cycloalkenyl isoptionally substituted with from 1 to 2 R_(f).

In another aspect, the invention provides a compound of Formula (II) ora pharmaceutically acceptable salt thereof, wherein:

R¹ is independently unsubstituted C₁₋₆ alkyl, C(═O)R^(a), —C(═O)OR^(a),—S(O)₂(R^(b)), or —C(═O)NR^(c)R^(d);

R² is independently H or unsubstituted C₁₋₃ alkyl;

R³ is H, unsubstituted C₁₋₂ alkyl, or X—R⁸, wherein X is an unbranchedC₂₋₄ alkylene, and R⁸ is CO₂R^(a), or —CONR^(c)R^(d);

R⁵ is independently selected from:

(i) C₃₋₆ cycloalkyl optionally substituted with from 1 to 2independently selected R^(f);

(ii) phenyl optionally substituted with from 1 to 3 R^(g);

(iii) heteroaryl including from 5 to 6 ring atoms, wherein from 1 to 3ring atoms are each independently selected from: N, NH, O, and S,wherein the heteroaryl is optionally substituted with from 1 to 3 R^(g);

(iv) C₁₋₆ alkyl optionally substituted with from 1 to 2 independentlyselected R^(h); and

(v) C₅₋₆ cycloalkenyl optionally substituted with from 1 to 2 R^(f);

R^(a) is H, C₁₋₄ alkyl optionally substituted with OH, C₃₋₆ cycloalkyl,phenyl, or heteroaryl including from 5 to 6 ring atoms, wherein from 1to 4 ring atoms are each independently selected from N, N(R^(e)), O, andS; and

R^(b) is C₁₋₄ alkyl.

In another aspect, the invention provides a compound of Formula (II) ora pharmaceutically acceptable salt thereof, wherein:

R¹ is independently C₁₋₆ alkyl, C(═O)R^(a), —C(═O)OR^(a), —S(O)₂(CH₃),or —C(═O)N(CH₃)₂;

R² is independently H, CH₃ or CH₂CH₃;

R³ is H, CH₃, or —(CH₂)₃C(═O)OCH₃;

R⁵ is independently CH₃, cyclopentyl, cyclopentenyl, phenyl,pyrazol-1-yl, or pyrazol-3-yl; and

R^(a) is H, CH₃, CH₂CH₃, CH(CH₃)₂, C(CH₃)₃, cyclopropyl, or thiazolyl.

In another aspect, the invention provides a compound of Formula (II) ora pharmaceutically acceptable salt thereof, wherein:

R¹ is independently C₁₋₆ alkyl, C(═O)R^(a), —C(═O)OR^(a), —S(O)₂(CH₃),or —C(═O)N(CH₃)₂;

R² is independently H, CH₃ or CH₂CH₃;

R³ is H or CH₃;

R⁵ is independently CH₃, cyclopentyl, cyclopentenyl, phenyl,pyrazol-1-yl, or pyrazol-3-yl; and

R^(a) is CH₃, CH₂CH₃, CH(CH₃)₂, C(CH₃)₃, or cyclopropyl.

In another aspect, the invention provides a compound of Formula (II) ora pharmaceutically acceptable salt thereof, wherein:

R¹ is independently CH₃, CH₂CH₃, CH(CH₃)₂, C(CH₃)₃, or C(═O)R^(a);

R² is independently H, CH₃ or CH₂CH₃;

R³ is H;

R⁵ is independently cyclopentyl, cyclopentenyl, phenyl, pyrazol-1-yl, orpyrazol-3-yl; and

R^(a) is CH₃, CH₂CH₃, CH(CH₃)₂, C(CH₃)₃, or cyclopropyl.

In another aspect, the invention provides a compound of Formula (II) ora pharmaceutically acceptable salt thereof, wherein:

R¹ is independently CH₃, CH₂CH₃, CH(CH₃)₂, or C(CH₃)₃;

R² is independently H, CH₃ or CH₂CH₃;

R³ is independently H, CH₃ or CH₂CH₃;

R⁴ is H; and

R⁵ is independently pyrazol-1-yl, pyrazol-3-yl or pyrazol-5-yl.

In another aspect, the invention provides a compound of Formula (II) ora pharmaceutically acceptable salt thereof, wherein:

R¹ is C(═O)R^(a);

R² is independently H, CH₃ or CH₂CH₃;

R³ is independently H, CH₃, CH₂CH₃ or CH₂CH₂OH;

R⁴ is H;

R⁵ is independently cyclopentyl, cyclopentenyl, thienyl, pyrazol-1-yl,pyrazol-3-yl, pyrazol-5-yl or (phenyl substituted with 0-1 C₁₋₄ alkyl);and

R^(a) is CH₃, CH₂CH₃, CH(CH₃)₂, C(CH₃)₃, —(CH)₂CH(CH₃)₂, cyclopropyl,1-methyl-1H-pyrrol-2-yl, or (phenyl substituted with C₁₋₄ alkoxy or Cl).

In some aspects, R¹ is unsubstituted C₁₋₆ alkyl, C(═O)R^(a),—C(═O)OR^(a), —S(O)₁₋₂(R^(b)), —S(O)₁₋₂NR^(c)R^(d) or —C(═O)NR^(c)R^(d).In other aspects, R¹ is unsubstituted C₁₋₆ alkyl, C(═O)R^(a),—C(═O)OR^(a), —S(O)₂(R^(b)), and —C(═O)NR^(c)R^(d). In other aspects, R¹is C₁₋₆ alkyl, C(═O)R^(a), —C(═O)OR^(a), —S(O)₂(CH₃), and —C(═O)N(CH₃)₂.In other aspects, R¹ is unsubstituted C₁₋₆ alkyl. In other aspects, R¹is CH₃ or CH₂CH₃. In other aspects, R¹ is CH₃. In other aspects, R¹ isCH₂CH₃. In other aspects, R¹ is C(═O)R^(a). In other aspects, R¹ isC(═O)CH₃. In other aspects, R¹ is C(═O)CH(CH₃)₂. In other aspects, R¹ isC(═O)CH₂(CH₃)₂. In other aspects, R¹ is C(═O)(cyclopropyl). In otheraspects, R¹ is —C(═O)OR^(a). In other aspects, R¹ is —C(═O)OC(CH₃)₃. Inother aspects, R¹ is —S(O)₁₋₂(R^(b)). In other aspects, R¹ is—S(O)₂(R^(b)). In other aspects, R¹ is —S(O)₂(CH₃). In other aspects, R¹is —S(O)₁₋₂NR^(c)R^(d). In other aspects, R¹ is —C(═O)NR^(c)R^(d). Inother aspects, R¹ is —C(═O)N(CH₃)₂.

In some aspects, R² is H or unsubstituted C₁₋₆ alkyl. In other aspects,R² is H or unsubstituted C₁₋₃ alkyl. In other aspects, R² is H, CH₃ orCH₂CH₃. In other aspects, R² is H. In other aspects, R² is CH₃ orCH₂CH₃. In other aspects, R² is CH₃. In other aspects, R² is CH₂CH₃.

In some aspects, R³ is H, unsubstituted C₁₋₂ alkyl, or X—R⁸, wherein Xis an unbranched C₂₋₆ alkylene, and R⁸ is CO₂R^(a), or —CONR^(c)R^(d).In other aspects, R³ is H, unsubstituted C₁₋₂ alkyl, or X—R⁸, wherein Xis an unbranched C₂₋₄ alkylene, and R⁸ is CO₂R^(a), or —CONR^(c)R^(d).In other aspects, R³ is H, CH₃, or —(CH₂)₃C(═O)OCH₃. In other aspects,R³ is H or unsubstituted C₁₋₂ alkyl. In other aspects, In other aspects,R³ is H or CH₃. In other aspects, In other aspects, R³ is H. In otheraspects, R³ is CH₃.

In some aspects, R⁴ is H or halo. In other aspects, R⁴ is H.

In some aspects, R⁵ is independently selected from: (i) —(C₀₋₃alkylene)-C₃₋₁₀ cycloalkyl, wherein the cycloalkyl is optionallysubstituted with from 1 to 4 independently selected R^(f); (ii) —(C₀₋₃alkylene)-heterocyclyl including from 3 to 10 ring atoms, wherein from 1to 3 ring atoms are each independently selected from: N(R^(e)), O, andS, wherein the heterocyclyl is optionally substituted with from 1 to 4R^(f); (iii) —(C₀₋₃ alkylene)-(C₆-C₁₀ aryl) optionally substituted withfrom 1 to 4 R^(g); (iv) —(C₀₋₃ alkylene)-heteroaryl including from 5 to10 ring atoms, wherein from 1 to 4 ring atoms are each independentlyselected from: N, NH, O, and S, wherein the heteroaryl is optionallysubstituted with from 1 to 3 R^(g); (v) C₁₋₆ alkyl optionallysubstituted with from 1-2 independently selected R^(h); and (iv) —(C₀₋₃alkylene)-C₃₋₁₀ cycloalkenyl, wherein the cycloalkenyl is optionallysubstituted with from 1 to 2 R^(f).

In other aspects, R⁵ is independently selected from: (i) C₃₋₆ cycloalkyloptionally substituted with from 1 to 2 independently selected R^(f);(ii) phenyl optionally substituted with from 1 to 3 R^(g); (iii)heteroaryl including from 5 to 6 ring atoms, wherein from 1 to 3 ringatoms are each independently selected from: N, NH, O, and S, wherein theheteroaryl is optionally substituted with from 1 to 3 R^(g); (iv) C₁₋₆alkyl optionally substituted with from 1 to 2 independently selectedR^(h); and (v) C₅₋₆ cycloalkenyl optionally substituted with from 1 to 2R^(f).

In other aspects, R⁵ is independently CH₃, cyclopentyl, cyclopentenyl,phenyl, pyrazol-1-yl, or pyrazol-3-yl. In other aspects, R⁵ is CH₃. Inother aspects, R⁵ is cyclopentyl or cyclopentenyl. In other aspects, R⁵is cyclopentyl. In other aspects, R⁵ is cyclopentenyl. In other aspects,R⁵ is phenyl. In other aspects, R⁵ is pyrazolyl. In other aspects, R⁵ ispyrazol-1-yl, or pyrazol-3-yl. In other aspects, R⁵ is pyrazol-1-yl. Inother aspects, R⁵ is pyrazol-3-yl.

In some aspects, (i) C₁₋₆ alkyl optionally substituted with from 1 to 2R^(h), (ii) —(C₀₋₃ alkylene)-C₃₋₁₀ cycloalkyl, wherein the cycloalkyl isoptionally substituted with from 1 to 2 R^(f); (iii) —(C₀₋₃alkylene)-phenyl optionally substituted with from 1 to 4 independentlyselected R^(g); or (v) —(C₀₋₃ alkylene)-heteroaryl including from 5 to10 ring atoms, wherein from 1 to 4 ring atoms are each independentlyselected from N, N(R^(e)), O, and S, wherein the heteroaryl isoptionally substituted with from 1 to 3 independently selected R. Inother aspects, R^(a) is (i) C₁₋₆ alkyl optionally substituted with from1 to 2 R^(h); (ii) —(C₀₋₃ alkylene)-C₃₋₁₀ cycloalkyl, wherein thecycloalkyl is optionally substituted with from 1 to 2 R^(f). In otheraspects, R^(a) is H, C₁₋₄ alkyl optionally substituted with OH, C₃₋₆cycloalkyl, phenyl, or heteroaryl including from 5 to 6 ring atoms,wherein from 1 to 4 ring atoms are each independently selected from N,N(R^(e)), O, and S. In other aspects, R^(a) is C₁₋₆ alkyl optionallysubstituted with from 1 to 2 R^(h). In other aspects, R^(a) is C₁₋₆alkyl. In other aspects, R^(a) is —(C₀₋₃ alkylene)-C₃₋₁₀ cycloalkyl,wherein the cycloalkyl is optionally substituted with from 1 to 2 R^(f).In other aspects, R^(a) is —C₃₋₁₀ cycloalkyl optionally substituted withfrom 1 to 2 R^(f). In other aspects, R^(a) is —C₃₋₆ cycloalkyl. In otheraspects, R^(a) is C₁₋₄ alkyl or C₃₋₆ cycloalkyl. In other aspects, R^(a)is CH₃, CH₂CH₃, CH₂(CH₃)₂, or cyclopropyl. In other aspects, R^(a) isCH₃, CH₂CH₃, or CH₂(CH₃)₂. In other aspects, R^(a) is cyclopropyl.

In another aspect, the compound of the invention is selected from:

or a pharmaceutically acceptable salt thereof.

In another aspect, the compound of the invention is selected from:

or a pharmaceutically acceptable salt thereof.

In another aspect, the compound of the invention is selected from:

or a pharmaceutically acceptable salt thereof.

In another aspect, the compound of the invention is selected from:

or a pharmaceutically acceptable salt thereof.

In another aspect, the compound of the invention is selected from:

or a pharmaceutically acceptable salt thereof.

In another aspect, the compound of the invention is selected from:

or a pharmaceutically acceptable salt thereof.

In another aspect, the compound of the invention is selected from:

or a pharmaceutically acceptable salt thereof.

In another aspect, the compound of the invention is selected from:

or a pharmaceutically acceptable salt thereof.

In another aspect, the compound of the invention is selected from:

or a pharmaceutically acceptable salt thereof.

In another aspect, the compound of the invention is

or a pharmaceutically acceptable salt thereof.

In another aspect, the compound of the invention is

or a pharmaceutically acceptable salt thereof.

In another aspect, the compound of the invention is

or a pharmaceutically acceptable salt thereof.

In another aspect, the compound of the invention is

or a pharmaceutically acceptable salt thereof.

In another aspect, the compound of the invention is

or a pharmaceutically acceptable salt thereof.

In another aspect, the compound of the invention is

or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides a compound of Formula (I) or apharmaceutically acceptable salt thereof, wherein:

R¹ and R², together with the nitrogen atom to which each is attachedforms a saturated or unsaturated ring including from 5 to 6 ring atoms,wherein the ring includes:

(a) from 3 to 5 ring carbon atoms, each of which is optionallysubstituted with from 1 to 2 independently selected R^(f); and

(b) from 0 to 1 ring heteroatom (in addition to the nitrogen atomattached to R¹ and R²), which is independently selected from: N,N(R^(e)), O, and S; and

provided that one of the 5 to 6 ring atoms is —C(O)—;

R³ is:

(i) H;

(ii) unsubstituted C₁₋₂ alkyl;

(iii) X—R⁸, wherein X is an unbranched C₁₋₆ alkylene, and R⁸ is —OH,C₁₋₄ alkoxy, —C₁₋₄ haloalkoxy, CO₂R^(a), —CONR^(c)R^(d), cyano, or—NR^(c′)R^(d′);

(iv) (C₁₋₃ alkylene)-(C₆-C₁₀ aryl), wherein the aryl is optionallysubstituted with from 1-3 substituents independently selected from C₁₋₆alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, and C₁₋₄ haloalkoxy; or

(v) (C₁₋₃ alkylene)heteroaryl including from 5-6 ring atoms, whereinfrom 1-4 ring atoms are each independently selected from N, N(R^(e)), O,and S, and wherein the heteroaryl is optionally substituted with from1-3 substituents independently selected from C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₁₋₄ alkoxy, and C₁₋₄ haloalkoxy;

R⁴ and R⁵ are each independently selected from:

(i) H;

(ii) halo;

(iv) —(C₀₋₃ alkylene)-C₃₋₁₀ cycloalkyl, wherein the cycloalkyl isoptionally substituted with from 1 to 4 independently selected R^(f);

(v) —(C₀₋₃ alkylene)-heterocyclyl including from 3 to 10 ring atoms,wherein from 1 to 3 ring atoms are each independently selected from:N(R^(e)), O, and S, wherein the heterocyclyl is optionally substitutedwith from 1 to 4 R^(f);

(vi) —(C₀₋₃ alkylene)-(C₆-C₁₀ aryl) optionally substituted with from 1to 4 R^(g);

(vii) —(C₀₋₃ alkylene)-heteroaryl including from 5 to 10 ring atoms,wherein from 1 to 4 ring atoms are each independently selected from: N,NH, O, and S, wherein the heteroaryl is optionally substituted with from1 to 3 R^(g);

(viii) C₁₋₆ alkyl optionally substituted with from 1-2 independentlyselected R^(h); and

(ix) —(C₀₋₃ alkylene)-C₄₋₁₀ cycloalkenyl, wherein the cycloalkenyl isoptionally substituted with from 1 to 2 R^(f);

each of R⁶ and R⁷ is independently H or unsubstituted C₁₋₂ alkyl;

R^(a) is:

(i) C₁₋₆ alkyl optionally substituted with from 1 to 2 R^(h), or

(ii) —(C₀₋₃ alkylene)-C₃₋₁₀ cycloalkyl, wherein the cycloalkyl isoptionally substituted with from 1 to 2 R^(f);

R^(b) is C₁₋₆ alkyl;

each occurrence of R^(c) and R^(d) is independently H or C₁₋₄ alkyl;

each occurrence of R^(e) is independently H or C₁₋₄ alkyl;

each occurrence of R is independently C₁₋₆ alkyl, C₁₋₄ haloalkyl, —OH,F, Cl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, cyano, or phenyl optionallysubstituted with from 1 to 4 R^(g);

each occurrence of R^(g) is independently halo, cyano, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₁₋₄ alkoxy, or C₁₋₄ haloalkoxy; and

each occurrence of R^(h) is independently —OH, F, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, or cyano.

In another aspect, the invention provides a compound of Formula (I) or apharmaceutically acceptable salt thereof, wherein:

R¹ and R², together with the nitrogen atom to which each is attachedforms a saturated or unsaturated ring including from 5 to 6 ring atoms,wherein the ring includes:

(a) from 3 to 5 ring carbon atoms, each of which is optionallysubstituted with from 1 to 2 independently selected R^(f), and

(b) from 0 to 1 ring heteroatom (in addition to the nitrogen atomattached to R¹ and R²), which is independently selected from: N,N(R^(e)), O, and S; and

provided that one of the ring atoms is —C(O)—;

R³ is: H, unsubstituted C₁₋₂ alkyl, X—R⁸, wherein X is an unbranchedC₁₋₆ alkylene, and R⁸ is CO₂R^(a), or —CONR^(c)R^(d);

R⁴ is independently H or halo;

R⁵ is independently selected from:

(i) H;

(ii) halo;

(iii) C₃₋₈ cycloalkyl optionally substituted with from 1 to 2independently selected R^(f);

(iv) phenyl optionally substituted with from 1 to 3 R^(g); and

(v) heteroaryl including from 5 to 9 ring atoms, wherein from 1 to 3ring atoms are each independently selected from: N, N(R^(e)), O, and S,wherein the heteroaryl is optionally substituted with from 1 to 3 R^(g);

(vi) C₁₋₆ alkyl optionally substituted with from 1 to 2 independentlyselected R^(h); and

(vii) C₅₋₆ cycloalkenyl optionally substituted with from 1 to 2 R^(f).

In another aspect, the invention provides a compound of Formula (I) or apharmaceutically acceptable salt thereof, wherein:

R¹ and R², together with the nitrogen atom to which each is attachedforms a saturated or unsaturated ring including from 5 to 6 ring atoms,wherein the ring includes:

(a) from 3 to 5 ring carbon atoms, each of which is optionallysubstituted with from 1 to 2 independently selected R^(f), and

(b) from 0 to 1 ring heteroatom (in addition to the nitrogen atomattached to R¹ and R²), which is independently selected from: N,N(R^(e)), and O; and

provided that one of the ring atoms is —C(O)—;

R³ is H, C₁₋₂ alkyl, or X—R⁸, wherein X is an unbranched C₂₋₆ alkylene,and R⁸ is CO₂(C₁₋₄ alkyl);

R⁴ is H;

R⁵ is independently selected from:

(i) halo;

(ii) C₃₋₇ cycloalkyl optionally substituted with from 1 to 2independently selected R^(f);

(iii) phenyl optionally substituted with from 1 to 3 R^(g);

(iv) heteroaryl including from 5 to 6 ring atoms, wherein from 1 to 3ring atoms are each independently selected from: N, NH, O, and S,wherein the heteroaryl is optionally substituted with from 1 to 3 R^(g);

each occurrence of R is independently C₁₋₆ alkyl, C₁₋₄ haloalkyl, —OH,F, Cl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, cyano, or phenyl.

In another aspect, the invention provides a compound of Formula (I) or apharmaceutically acceptable salt thereof, wherein:

R¹ and R², together with the nitrogen atom to which each is attachedforms

R³ is H, unsubstituted C₁₋₂ alkyl, or X—R⁸, wherein X is an unbranchedC₂₋₄ alkylene, and R^(g) is CO₂(C₁₋₄ alkyl);

R⁴ is H;

R⁵ is independently Br, C₆₋₇ cycloalkyl, (phenyl optionally substitutedwith one to two substituents selected from halo, C₁₋₂ alkyl, C₁₋₂alkoxy, and CN) or (a heteroaryl selected from pyrazolyl, theinyl andpyridyl, wherein each of the heteroaryl is optionally substituted withone to two substituents selected from halo, C₁₋₂ alkyl, C₁₋₂ alkoxy, andCN);

R⁶ is H or unsubstituted C₁₋₂ alkyl; and

R⁷ is H.

In another aspect, the invention provides a compound of Formula (I) or apharmaceutically acceptable salt thereof, wherein:

R¹ and R², together with the nitrogen atom to which each is attachedforms

R³ is H;

R⁴ is H;

R⁵ is independently Br, cyclohexyl, pyrazol-1-yl, pyrazol-3-yl,thien-2-yl, thien-3-yl, (phenyl optionally substituted with onesubstituent selected from F, Cl, CH₃, OCH₃, and CN), or (pyrid-3-yloptionally substituted with one substituent selected from F and Cl);

R⁶ is H or CH₃; and

R⁷ is H.

In another aspect, the invention provides a compound of Formula (I) or apharmaceutically acceptable salt thereof, wherein:

R¹ and R², together with the nitrogen atom to which each is attachedforms

R³ is independently H, CH₃, CH₂CH₃ or CH₂CH₂OH;

R⁴ is H;

R⁵ is independently cyclohexyl, pyrazol-1-yl, pyrazol-3-yl, thien-2-yl,thien-3-yl, (phenyl optionally substituted with one substituent selectedfrom F, Cl, CH₃, OCH₃, and CN), or (pyrid-3-yl optionally substitutedwith one substituent selected from F and Cl);

R⁶ is H; and

R⁷ is H.

In another aspect, the compound of the invention is selected from:

or a pharmaceutically acceptable salt thereof.

In another aspect, the compound of the invention is selected from:

or a pharmaceutically acceptable salt thereof.

In another aspect, the compound of the invention is selected from:

or a pharmaceutically acceptable salt thereof.

In another aspect, the compound of the invention is selected from:

or a pharmaceutically acceptable salt thereof.

In another aspect, the compound of the invention is

or a pharmaceutically acceptable salt thereof.

In another aspect, the compound of the invention is

or a pharmaceutically acceptable salt thereof.

In some aspects, R¹ and R², together with the nitrogen atom to whicheach is attached forms a saturated or unsaturated ring including from 5to 6 ring atoms, wherein the ring includes: (a) from 3 to 5 ring carbonatoms, each of which is optionally substituted with from 1 to 2independently selected R^(f), and (b) from 0 to 1 ring heteroatom (inaddition to the nitrogen atom attached to R¹ and R²), which isindependently selected from: N, N(R^(e)), O, and S; and provided thatone of the ring atoms is —C(O)—. In other aspects, R¹ and R², togetherwith the nitrogen atom to which each is attached forms a saturated orunsaturated ring including from 5 to 6 ring atoms, wherein the ringincludes: (a) from 3 to 5 ring carbon atoms, each of which is optionallysubstituted with from 1 to 2 independently selected R^(f), and (b) from0 to 1 ring heteroatom (in addition to the nitrogen atom attached to R¹and R²), which is independently selected from: N, N(R^(e)), O, and S;and provided that one of the ring atoms is —C(O)—. In other aspects, R¹and R², together with the nitrogen atom to which each is attached formsa saturated or unsaturated ring including from 5 to 6 ring atoms,wherein the ring includes: (a) from 3 to 5 ring carbon atoms, each ofwhich is optionally substituted with from 1 to 2 independently selectedR^(f), and (b) from 0 to 1 ring heteroatom (in addition to the nitrogenatom attached to R¹ and R²), which is independently selected from: N,N(R^(e)), and O; and provided that one of the ring atoms is —C(O)—. Inother aspects, R¹ and R², together with the nitrogen atom to which eachis attached forms

In other aspects, R¹ and R² together with the nitrogen atom to whicheach is attached forms

In another aspect, the invention provides a compound selected from theexemplified examples or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides a compound selected from anysubset list of compounds or a single compound from the exemplifiedexamples within the scope of any of the above aspects.

The skilled artisan will recognize that some chemical structuresdescribed herein may be represented on paper by one or more otherresonance forms; or may exist in one or more other tautomeric forms,even when kinetically, the artisan recognizes that such tautomeric formsrepresent only a very small portion of a sample of such compound(s).Such compounds are clearly contemplated within the scope of thisdisclosure, though such resonance forms or tautomers are not explicitlyrepresented herein.

In some embodiments, the compound of Formula I is a compound selectedfrom compounds in Table 1 below. The biological assays used to test thecompounds are discussed in the examples section. Key to activity ranges:A=≤1 μM; B=>1 μM, ≤20 μM; C=>20 μM, ≤100 μM; D=>100 μM.

TABLE 1 hNLRP3 Agonist TLR7 TLR8 EC₅₀ EC₅₀ EC₅₀ LCMS Structure Compound(μM) (μM) (μM) [M + H]⁺

101 0.27 D D 308.3

102 1.60 D D 336.3

103 0.52 D D 424.3

104 0.60 D D 298.1

105 0.69 348.2

106 0.70 D D 322.1

107 0.64 350.3

108 0.87 D D 386.3

109 0.88 D D 408.3

110 0.90 D D 379.3

111 0.72 D D 336.3

112 1.28 D D 350.1

113 0.56 322.3

114 1.04 D D 419.4

115 0.90 D D 372.1

116 1.16 358.0

117 1.26 C D 362.4

118 1.36 D D 376.2

119 1.38 D D 372.1

120 1.69 D D 362.2

121 1.82 D D 364.2

122 1.40 D D 350.2

123 1.9 D D 376.2

124 2.4 D D 386.2

125 2.1 D D 364.2

126 2.1 412.4

128 2.9 D D 365.2

129 3.6 D D 336.2

130 3.3 D D 351.2

131 3.5 D D 280.3

132 3.5 D D 350.9

133 3.5 366.3

135 4.6 409.2

136 4.8 D D 362.2

137 5.4 424.4

138 6.7 C D 373.2

140 7.3 D D 364.2

141 9.0 D D 316.1

142 9.1 D D 380.2

143 9.4 C D 316.1

153 12.0 C D 393.4

154 16.1 D C 272.0

155 17.4 D D 408.2

157 23.4 C C 398.2

158 24.5 D D 314.3

159 25.9 D D 352.0

162 42.0 D D 308.3

163 48.4 C D 350.2

164 4.6 D D 384.2

165 0.19 D D 360.2

166 3.4 D D 361.2

167 58 D D 361.2

168 101 D D 378.2

169 92 D D 392.2

170 7.9 C D 326.2

171 3.2 B D 312.2

172 2.1 B D 326.2

173 0.84 D D 352.2

175 2.6 D D 379.2

176 25.7 D D 284.1

177 7.4 D D 362.1

179 12.5 D D 318.1

180 1.5 D D 350.2

182 5.9 D 376.1

183 0.52 D D 350.3

187 64 B C 270.2

188 5.7 D D 370.2

190 10.3 D D 444.4

191 65 D D 441.2

194 7.9 D D 362.1

196 32.7 D D 488.2

197 13.7 D D 318.0

198 24.2 D D 434.2

199 D D 369.3

200 11.9 D D 378.0

201 20.8 D D 398.2

202 35.9 D D 474.1

203 10.8 D D 390.4

204 6.7 D D 424.0

205 36 D D 483.4

207 73 D D 350.1

209 22 D D 530.2

210 61 D D 463.2

211 40 D D 582.4

212 85 D D 524.4

213 17.6 D D 477.2

214 51.5 D D 517.2

215 18.2 D D 473.1

216 6.6 D D 416.2

217 96 D D 417.2

218 1.2 D D 464.2

219 2.0 D D 418.2

220 51 D D 473.2

221 85 D D 486.4

222 42 D D 457.2

223 77 C D 531.3

225 10.9 D B 321.9

226 85 D D 509.4

227 22.7 C D 410.3

228 93 D D 565.3

229 12.3 D D 452.2

230 4.5 D D 388.2

233 120 B D 256.1

278 10.8 C D 282.1

279 7.5 D D 359.1

280 0.22 D D 358.2

281 1.4 D D 392.1

282 4.8 D D 372.2

283 6.5 D D 388.2

284 0.86 D D 376.1

285 5.7 D D 392.1

286 0.61 D D 372.2

287 1.08 D D 388.2

288 10.1 D D 383.1

289 1.58 D D 376.1

291 0.11 D D 372.2

292 4.48 D D 388.2

294 4.6 C D 360.0

295 1.20 D D 348.1

296 5.1 D D 362.2

298 21 B D 366.2

301 2.93 D D 362.2

302 0.93 D D 364.2

303 11.1 C C 373.8

304 36.4 389.2

307 12.3 377.1

308 1.06 364.1

309 0.24 D D 364.1

315 1.18 D D 383.2

316 1.10 D D 436.1

319 6.2 D D 389.2

320 1.5 D D 393.1

321 4.5 C D 393.1

324 6.7 D D 427.1

326 2.7 D D 384.1

327 13 D D 384.1

328 4.1 D D 393.1

330 1.6 D D 377.1

331 3.2 D D 377.1

332 3.3 D D 378.2

333 1.9 D D 435.2

335 6.5 D D 382.2

337 80 D D 429.2

340 50 D D 472.4

341 2.1 D D 462.2

342 3.3 D D 459.3

345 64 453.2

346 17.3 D D 296.1

347 41 D D 396.2

348 0.89 D D 308.0

349 0.60 D D 322.1

350 10 377.2

351 2.17 364.2

352 2.23 362.1

357 0.64 D D 424.4

358 0.63 D D 424.4

363 5.8 D D 426.4

365 5.0 D D 350.2

368 3.9 D D 363.2

370 4.8 D D 352.3

372 8.3 D D 351.3

375 2.4 D D 365.2

376 3.6 D D 398.3

377 4.3 D D 405.3

379 2.0 D D 336.3

383 3.6 D D 393.4

393 7.11 D D 422.2

397 1.05 D D 424.4

398 1.22 D D 308.3

399 1.06 D D 324.2

400 1.79 D D 324.2

401 1.23 D D 294.3

402 1.31 D D 294.3

403 3.66 D D 483.3

404 2.50 D D 590.3

405 2.19 D D 352.3

406 1.37 D D 366.1

407 6.55 D D 424.2

408 5.23 D D 424.2

409 2.36 D D 546.5

414 3.83 D D 479.4

417 7.4 D D 392.4

419 0.91 D D 366.3

420 0.19 D D 422.4

421 0.24 322.0

422 0.28 >10 >10 374.1

423 0.62 D D

424 0.79 D 424.2

425 0.44 D 366.2

426 4.3 D

427 5.0 D D 379.0

428 5.1 D

429 5.8 D 350.2

430 7.45 D >10 418.1

431 8.67 D >10 434.1

432 ~10 377.2

433 11.5 474.3

434 15.5 >30 >30

435 19.3 D 404.2

436 1.3 >50 >50 390.0

437 1.1 D D 440.4

438 4.2 D D 413.0

439 5.7 D D 413.2

440 18.4 D D 408.4

441 0.69 D >62 442.0

442 2.6 D D 414.0

443 0.86 D >62 426.0

444 0.93 D B 454.1

445 0.74 D >62 406.1

446 0.67 D D 415.2

447 1.5 D B 440.2

448 2.0 D D 419.3

449 0.90 D C 446.0

450 4.5 D D 413.0

451 1.3 D C 465.2

452 1.2 D >62 446.0

453 0.71 D D 364.1

454 0.74 D D 407.1

455 2.0 D D 421.4

456 2.2 D D 407.1

457 6.6 D D 379.3

458 2.1 D D 415.0

459 6.7 D D 413.9

460 1.5 D >62 414.0

462 5.5 D D 352.3

463 0.22 D D 392.2

464 0.24 D D 336.3

465 1.0 D D 376.2

466 1.1 D D 376.2

467 1.2 D D 336.3

468 2.1 D D 352.1

469 0.67 D D 408.0

470 0.69 D D 424.1

471 1.2 D D 368.1

472 0.43 D D 393.9

473 0.22 D D 392.3

474 1.2 D D 378.3

475 23 D D 408.1

476 6.1 D D 394.1

477 6.3 D D 352.1

478 3.7 D D 408.1

479 0.67 D D 378.0

480 1.9 D D 408.0

481 0.63 D D 392.2

482 0.43 D D 410.1and pharmaceutically acceptable salts thereof.

Pharmaceutical Compositions and Administration

General

In some embodiments, a chemical entity (e.g., a compound that modulates(e.g., agonizes or partially agonizes) NLRP3, or a pharmaceuticallyacceptable salt, and/or hydrate, and/or cocrystal, and/or drugcombination thereof) is administered as a pharmaceutical compositionthat includes the chemical entity and one or more pharmaceuticallyacceptable excipients, and optionally one or more additional therapeuticagents as described herein.

In some embodiments, a pharmaceutical composition comprising a compoundof the present invention or a salt thereof, and one or morepharmaceutically acceptable excipients. In certain embodiments, apharmaceutical composition comprising a compound of the presentinvention or a pharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable excipients. In certain embodiments, apharmaceutical composition comprising a therapeutically effective amountof a compound of the present invention or a pharmaceutically acceptablesalt thereof, and one or more pharmaceutically acceptable excipients.

In some embodiments, the chemical entities can be administered incombination with one or more conventional pharmaceutical excipients.Pharmaceutically acceptable excipients include, but are not limited to,ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifyingdrug delivery systems (SEDDS) such as d-α-tocopherol polyethylene glycol1000 succinate, surfactants used in pharmaceutical dosage forms such asTweens, poloxamers or other similar polymeric delivery matrices, serumproteins, such as human serum albumin, buffer substances such asphosphates, tris, glycine, sorbic acid, potassium sorbate, partialglyceride mixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium-chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethyl cellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, andwool fat. Cyclodextrins such as α-, β, and γ-cyclodextrin, or chemicallymodified derivatives such as hydroxyalkylcyclodextrins, including 2- and3-hydroxypropyl-β-cyclodextrins, or other solubilized derivatives canalso be used to enhance delivery of compounds described herein. Dosageforms or compositions containing a chemical entity as described hereinin the range of 0.005% to 100% with the balance made up from non-toxicexcipient may be prepared. The contemplated compositions may contain0.001%-100% of a chemical entity provided herein, in one embodiment0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%.Actual methods of preparing such dosage forms are known, or will beapparent, to those skilled in this art; for example, see Remington: TheScience and Practice of Pharmacy, 22^(nd) Edition (Pharmaceutical Press,London, U K. 2012).

Routes of Administration and Composition Components

In some embodiments, the chemical entities described herein or apharmaceutical composition thereof can be administered to subject inneed thereof by any accepted route of administration. Acceptable routesof administration include, but are not limited to, buccal, cutaneous,endocervical, endosinusial, endotracheal, enteral, epidural,interstitial, intra-abdominal, intra-arterial, intrabronchial,intrabursal, intracerebral, intracisternal, intracoronary, intradermal,intraductal, intraduodenal, intradural, intraepidermal, intraesophageal,intragastric, intragingival, intraileal, intralymphatic, intramedullary,intrameningeal, intramuscular, intraovarian, intraperitoneal,intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial,intratesticular, intrathecal, intratubular, intratumoral, intrauterine,intravascular, intravenous, nasal, nasogastric, oral, parenteral,percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous,sublingual, submucosal, topical, transdermal, transmucosal,transtracheal, ureteral, urethral and vaginal. In certain embodiments, apreferred route of administration is parenteral (e.g., intratumoral). Incertain embodiments, a preferred route of administration is systemic.

Compositions can be formulated for parenteral administration, e.g.,formulated for injection via the intravenous, intramuscular,sub-cutaneous, or even intraperitoneal routes. Typically, suchcompositions can be prepared as injectables, either as liquid solutionsor suspensions; solid forms suitable for use to prepare solutions orsuspensions upon the addition of a liquid prior to injection can also beprepared; and the preparations can also be emulsified. The preparationof such formulations will be known to those of skill in the art in lightof the present disclosure.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions; formulations including sesame oil,peanut oil, or aqueous propylene glycol; and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases the form must be sterile and must be fluid tothe extent that it may be easily injected. It also should be stableunder the conditions of manufacture and storage and must be preservedagainst the contaminating action of microorganisms, such as bacteria andfungi.

The carrier also can be a solvent or dispersion medium containing, forexample, water, ethanol, polyol (for example, glycerol, propyleneglycol, and liquid polyethylene glycol, and the like), suitable mixturesthereof, and vegetable oils. The proper fluidity can be maintained, forexample, by the use of a coating, such as lecithin, by the maintenanceof the required particle size in the case of dispersion, and by the useof surfactants. The prevention of the action of microorganisms can bebrought about by various antibacterial and antifungal agents, forexample, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, andthe like. In many cases, it will be preferable to include isotonicagents, for example, sugars or sodium chloride. Prolonged absorption ofthe injectable compositions can be brought about by the use in thecompositions of agents delaying absorption, for example, aluminummonostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the activecompounds in the required amount in the appropriate solvent with variousof the other ingredients enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the various sterilized active ingredients into a sterilevehicle which contains the basic dispersion medium and the requiredother ingredients from those enumerated above. In the case of sterilepowders for the preparation of sterile injectable solutions, thepreferred methods of preparation are vacuum-drying and freeze-dryingtechniques, which yield a powder of the active ingredient, plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof.

Intratumoral injections are discussed, e.g., in Lammers, et al., “Effectof Intratumoral Injection on the Biodistribution and the TherapeuticPotential of HPMA Copolymer-Based Drug Delivery Systems” Neoplasia.10:788-795 (2006).

Pharmacologically acceptable excipients usable in the rectal compositionas a gel, cream, enema, or rectal suppository, include, withoutlimitation, any one or more of cocoa butter glycerides, syntheticpolymers such as polyvinylpyrrolidone, PEG (like PEG ointments),glycerine, glycerinated gelatin, hydrogenated vegetable oils,poloxamers, mixtures of polyethylene glycols of various molecularweights and fatty acid esters of polyethylene glycol Vaseline, anhydrouslanolin, shark liver oil, sodium saccharinate, menthol, sweet almondoil, sorbitol, sodium benzoate, anoxid SBN, vanilla essential oil,aerosol, parabens in phenoxyethanol, sodium methyl p-oxybenzoate, sodiumpropyl p-oxybenzoate, diethylamine, carbomers, carbopol,methyloxybenzoate, macrogol cetostearyl ether, cocoyl caprylocaprate,isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum,carboxy-metabisulfite, sodium edetate, sodium benzoate, potassiummetabisulfite, grapefruit seed extract, methyl sulfonyl methane (MSM),lactic acid, glycine, vitamins, such as vitamin A and E and potassiumacetate.

In certain embodiments, suppositories can be prepared by mixing thechemical entities described herein with suitable non-irritatingexcipients or carriers such as cocoa butter, polyethylene glycol or asuppository wax which are solid at ambient temperature but liquid atbody temperature and therefore melt in the rectum and release the activecompound. In other embodiments, compositions for rectal administrationare in the form of an enema.

In other embodiments, the compounds described herein or a pharmaceuticalcomposition thereof are suitable for local delivery to the digestive orGI tract by way of oral administration (e.g., solid or liquid dosageforms).

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the chemicalentity is mixed with one or more pharmaceutically acceptable excipients,such as sodium citrate or dicalcium phosphate and/or: a) fillers orextenders such as starches, lactose, sucrose, glucose, mannitol, andsilicic acid, b) binders such as, for example, carboxymethylcellulose,alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c)humectants such as glycerol, d) disintegrating agents such as agar-agar,calcium carbonate, potato or tapioca starch, alginic acid, certainsilicates, and sodium carbonate, e) solution retarding agents such asparaffin, f) absorption accelerators such as quaternary ammoniumcompounds, g) wetting agents such as, for example, cetyl alcohol andglycerol monostearate, h) absorbents such as kaolin and bentonite clay,and i) lubricants such as talc, calcium stearate, magnesium stearate,solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof.In the case of capsules, tablets and pills, the dosage form may alsocomprise buffering agents. Solid compositions of a similar type may alsobe employed as fillers in soft and hard-filled gelatin capsules usingsuch excipients as lactose or milk sugar as well as high molecularweight polyethylene glycols and the like.

In one embodiment, the compositions will take the form of a unit dosageform such as a pill or tablet and thus the composition may contain,along with a chemical entity provided herein, a diluent such as lactose,sucrose, dicalcium phosphate, or the like; a lubricant such as magnesiumstearate or the like; and a binder such as starch, gum acacia,polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or thelike. In another solid dosage form, a powder, marume, solution orsuspension (e.g., in propylene carbonate, vegetable oils, PEG's,poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin orcellulose base capsule). Unit dosage forms in which one or more chemicalentities provided herein or additional active agents are physicallyseparated are also contemplated; e.g., capsules with granules (ortablets in a capsule) of each drug; two-layer tablets; two-compartmentgel caps, etc. Enteric coated or delayed release oral dosage forms arealso contemplated.

Other physiologically acceptable compounds include wetting agents,emulsifying agents, dispersing agents or preservatives that areparticularly useful for preventing the growth or action ofmicroorganisms. Various preservatives are well known and include, forexample, phenol and ascorbic acid.

In certain embodiments the excipients are sterile and generally free ofundesirable matter. These compositions can be sterilized byconventional, well-known sterilization techniques. For various oraldosage form excipients such as tablets and capsules sterility is notrequired. The USP/NF standard is usually sufficient.

In certain embodiments, solid oral dosage forms can further include oneor more components that chemically and/or structurally predispose thecomposition for delivery of the chemical entity to the stomach or thelower GI; e.g., the ascending colon and/or transverse colon and/ordistal colon and/or small bowel. Exemplary formulation techniques aredescribed in, e.g., Filipski, K. J., et al., Current Topics in MedicinalChemistry, 2013, 13, 776-802, which is incorporated herein by referencein its entirety.

Examples include upper-GI targeting techniques, e.g., Accordion Pill(Intec Pharma), floating capsules, and materials capable of adhering tomucosal walls.

Other examples include lower-GI targeting techniques. For targetingvarious regions in the intestinal tract, several enteric/pH-responsivecoatings and excipients are available. These materials are typicallypolymers that are designed to dissolve or erode at specific pH ranges,selected based upon the GI region of desired drug release. Thesematerials also function to protect acid labile drugs from gastric fluidor limit exposure in cases where the active ingredient may be irritatingto the upper GI (e.g., hydroxypropyl methylcellulose phthalate series,Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate,hydroxypropyl methylcellulose acetate succinate, Eudragit series(methacrylic acid-methyl methacrylate copolymers), and Marcoat). Othertechniques include dosage forms that respond to local flora in the GItract, Pressure-controlled colon delivery capsule, and Pulsincap.

Ocular compositions can include, without limitation, one or more of anyof the following: viscogens (e.g., Carboxymethylcellulose, Glycerin,Polyvinylpyrrolidone, Polyethylene glycol); Stabilizers (e.g., Pluronic(triblock copolymers), Cyclodextrins); Preservatives (e.g., Benzalkoniumchloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zincchloride; Alcon Laboratories, Inc.), Purite (stabilized oxychlorocomplex; Allergan, Inc.)).

Topical compositions can include ointments and creams. Ointments aresemisolid preparations that are typically based on petrolatum or otherpetroleum derivatives. Creams containing the selected active agent aretypically viscous liquid or semisolid emulsions, often eitheroil-in-water or water-in-oil. Cream bases are typically water-washable,and contain an oil phase, an emulsifier and an aqueous phase. The oilphase, also sometimes called the “internal” phase, is generallycomprised of petrolatum and a fatty alcohol such as cetyl or stearylalcohol; the aqueous phase usually, although not necessarily, exceedsthe oil phase in volume, and generally contains a humectant. Theemulsifier in a cream formulation is generally a nonionic, anionic,cationic or amphoteric surfactant. As with other carriers or vehicles,an ointment base should be inert, stable, nonirritating andnon-sensitizing.

In any of the foregoing embodiments, pharmaceutical compositionsdescribed herein can include one or more one or more of the following:lipids, interbilayer crosslinked multilamellar vesicles, biodegradeablepoly(D,L-lactic-co-glycolic acid) [PLGA]-based or poly anhydride-basednanoparticles or microparticles, and nanoporous particle-supported lipidbilayers.

Dosages

The dosages may be varied depending on the requirement of the patient,the severity of the condition being treating and the particular compoundbeing employed. Determination of the proper dosage for a particularsituation can be determined by one skilled in the medical arts. Thetotal daily dosage may be divided and administered in portionsthroughout the day or by means providing continuous delivery.

In some embodiments, the compounds described herein are administered ata dosage of from about 0.001 mg/Kg to about 500 mg/Kg (e.g., from about0.001 mg/Kg to about 200 mg/Kg; from about 0.01 mg/Kg to about 200mg/Kg; from about 0.01 mg/Kg to about 150 mg/Kg; from about 0.01 mg/Kgto about 100 mg/Kg; from about 0.01 mg/Kg to about 50 mg/Kg; from about0.01 mg/Kg to about 10 mg/Kg; from about 0.01 mg/Kg to about 5 mg/Kg;from about 0.01 mg/Kg to about 1 mg/Kg; from about 0.01 mg/Kg to about0.5 mg/Kg; from about 0.01 mg/Kg to about 0.1 mg/Kg; from about 0.1mg/Kg to about 200 mg/Kg; from about 0.1 mg/Kg to about 150 mg/Kg; fromabout 0.1 mg/Kg to about 100 mg/Kg; from about 0.1 mg/Kg to about 50mg/Kg; from about 0.1 mg/Kg to about 10 mg/Kg; from about 0.1 mg/Kg toabout 5 mg/Kg; from about 0.1 mg/Kg to about 1 mg/Kg; from about 0.1mg/Kg to about 0.5 mg/Kg).

Regimens

The foregoing dosages can be administered on a daily basis (e.g., as asingle dose or as two or more divided doses) or non-daily basis (e.g.,every other day, every two days, every three days, once weekly, twiceweeks, once every two weeks, once a month).

In some embodiments, the period of administration of a compounddescribed herein is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks,11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9months, 10 months, 11 months, 12 months, or more. In a furtherembodiment, a period of during which administration is stopped is for 1day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11months, 12 months, or more. In an embodiment, a therapeutic compound isadministered to an individual for a period of time followed by aseparate period of time. In another embodiment, a therapeutic compoundis administered for a first period and a second period following thefirst period, with administration stopped during the second period,followed by a third period where administration of the therapeuticcompound is started and then a fourth period following the third periodwhere administration is stopped. In an aspect of this embodiment, theperiod of administration of a therapeutic compound followed by a periodwhere administration is stopped is repeated for a determined orundetermined period of time. In a further embodiment, a period ofadministration is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks,11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9months, 10 months, 11 months, 12 months, or more. In a furtherembodiment, a period of during which administration is stopped is for 1day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11months, 12 months, or more.

Methods of Treatment

In some embodiments, methods for treating a subject having condition,disease or disorder in which an increase in NLRP3 signaling may correcta deficiency in innate immune activity (e.g., a condition, disease ordisorder associated with an insufficient immune response) thatcontributes to the pathology and/or symptoms and/or progression of thecondition, disease or disorder (e.g., cancer) are provided.

Indications

In any of the methods described herein, the subject can have a cancer.In some examples of any of the methods described herein, the mammal hasbeen identified as having a cancer, or has been diagnosed as having acancer.

Non-limiting examples of cancer include: acute myeloid leukemia,adrenocortical carcinoma, Kaposi sarcoma, lymphoma, anal cancer,appendix cancer, teratoid/rhabdoid tumor, basal cell carcinoma, bileduct cancer, bladder cancer, bone cancer, brain cancer, breast cancer,bronchial tumor, carcinoid tumor, cardiac tumor, cervical cancer,chordoma, chronic lymphocytic leukemia, chronic myeloproliferativeneoplasm, colon cancer, colorectal cancer, craniopharyngioma,endometrial cancer, ependymoma, esophageal cancer,esthesioneuroblastoma, Ewing sarcoma, eye cancer, fallopian tube cancer,gallbladder cancer, gastrointestinal carcinoid tumor, gastrointestinalstromal tumor, germ cell tumor, hairy cell leukemia, head and neckcancer, heart cancer, liver cancer, hypopharngeal cancer, pancreaticcancer, kidney cancer, laryngeal cancer, chronic myelogenous leukemia,lip and oral cavity cancer, lung cancer, melanoma, Merkel cellcarcinoma, mesothelioma, mouth cancer, oral cancer, osteosarcoma,ovarian cancer, penile cancer, pharyngeal cancer, prostate cancer,rectal cancer, salivary gland cancer, skin cancer, small intestinecancer, soft tissue sarcoma, testicular cancer, throat cancer, thyroidcancer, urethral cancer, uterine cancer, vaginal cancer, and vulvarcancer.

In certain embodiments, non-limiting examples of cancer include: breastcancer, colon cancer, rectal cancer, colorectal cancer, pancreaticcancer, and prostate cancer.

Methods for diagnosing a subject as having a cancer or identifying amammal as having a cancer are well known in the art. For example, amedical professional (e.g., a physician, a physician's assistant, or atechnician) can diagnose cancer in a mammal by observing one or moresymptoms of cancer in a mammal. Non-limiting examples of symptoms ofcancer include: fatigue, lump or area of thickening felt under the skin,weight change, jaundice, darkening or redness of the skin, sores thatwon't heal, changes to existing moles, changes in bowel or bladderhabits, persistent cough or trouble breathing, difficulty swallowing,hoarseness, persistent indigestion or discomfort after eating,persistent, unexplained muscle or joint pain, persistent, unexplainedfevers or night sweats, and unexplained bleeding or bruising. Methods ofdiagnosing a subject as having a cancer or identifying a subject ashaving a cancer can further include performing one or more diagnostictests (e.g., performing one or more diagnostic tests on a biopsy or ablood sample).

In some examples of any of the methods described herein, a subject canbe a subject having a cancer, a subject diagnosed as having a cancer, ora subject identified as having a cancer that has been unresponsive to apreviously administered treatment for cancer. Diagnostic tests fordiagnosing a subject as having a cancer or identifying a mammal ashaving a cancer are known in the art.

In some embodiments, methods for treating a subject having condition,disease or disorder in which an increase in NLRP3 signaling may correcta deficiency in innate immune activity (e.g., a condition, disease ordisorder associated with an insufficient immune response) thatcontributes to the pathology and/or symptoms and/or progression of thecondition, disease or disorder (e.g., cancer) are provided.

In some embodiments, the present invention provides a method of treatingcancer, wherein the cancer can be any cancer that does not elicit anoptimal innate immune system response.

Innate immune system refers to a part of the immune system consisting ofcells that react to threats for the organism like infections or cancerin an antigen-non-specific way and stimulate the adaptive,antigen-specific immune system. In general, complete removal of thethreat and long-lasting protection (=immunity) requires activity of theadaptive, antigen-specific immune system that in turn depends onstimulation by the innate immune system.

In some embodiments, the present invention provides a method of treatingcase, the cancer is selected based on resistance to T-cell checkpointinhibition, either independent of cancer type and based on failure torespond to previous T-cell checkpoint inhibitor therapy or based oncancer type that is generally resistant to T-cell checkpoint inhibitortherapy such as hormone receptor positive breast cancer, microsatellitestable colon or rectal cancer, pancreatic cancer and prostate cancer.

In certain other embodiments, the present invention provides a method oftreating cancer comprising an NLPR3 agonist of the present invention totreat non-inflamed tumors with low CD8+ T-cell infiltration to enhancetumor immunogenicity and promote inflammatory responses. For example,the combination may be used to treat a solid tumor based on results of abiopsy that demonstrated low CD8+ T-cell infiltration or low expressionof genes produced by CD8+ T-cells.

Resistance to T-cell checkpoint inhibition refers to cancer progressionon therapy or lack of response within 6 months of therapy according toconsensus response criteria for the respective cancer, such as RECISTI.1for most solid tumors.

T-cell infiltration refers to percent of T-cells of all nucleated cellsby immunohistochemistry of tumor biopsy specimens.

CD8+ T-cell infiltration refers to percent of CD8+ cells of allnucleated cells by immunohistochemistry of tumor biopsy specimens.

In addition to immunohistochemistry for quantifying CD8+ T-cells inbiopsy specimens, expression of genes produced by CD8+ T-cells likeinterferon-γ can be measured by quantifying mRNA using for example nextgeneration sequencing and inform about CD8+ T-cell infiltration.Thresholds for low and high CD8+ T-cell infiltration byimmunohistochemistry of mRNA quantifying techniques are being developedby various groups and take the spectrum of CD8+ T-cell infiltrationacross cancers as well as for specific cancers into account.

In any of the methods described herein, the subject can have aninfectious disease. In some examples of any of the methods describedherein, the subject has been identified as having an infectious disease,or has been diagnosed as having an infectious disease. For example, aninfectious disease can be caused by a bacterium, virus, fungus,parasite, or a mycobacterium.

Non-limiting examples of infectious disease include: Acinobacterinfection, actinomycosis, African sleeping sickness, acquiredimmunodeficiency syndrome, amebiasis, anaplasmosis, anthrax,Arcanobacterium haemolyticum infection, Argentine hemorrhagic fever,ascariasis, aspergillosis, astrovirus infection, babesiosis, Bacilluscereus infection, bacterial pneumonia, bacterial vaginosis, Bacteroidesinfection, balantidiasis, Baylisascaris infection, BK virus infection,black piedra, Blastocystic hominis infection, blastomycosis, Bolivianhemorrhagic fever, botulism, Brazilian hemorrhagic fever, brucellosis,bubonic plaque, Burkholderi infection, Buruli ulcer, Calicivirusinfection, camptobacteriosis, candidiasis, cat-scratch disease,cellulitis, Chagas disease, chancroid, chickenpox, chikungunya,chlamydia, Chlamydophila pneumoniae infection, cholera,chromoblastomycosis, clonorchiasis, Clostridium difficile infection,coccidioidomycosis, Colorado tick fever, common cold, Creutzfeldt-Jakobdisease, Crimean-Congo hemorrhagic fever, crytococcosis,cryptosporidiosis, cutaneous larva migrans, cyclosporiasis,cysticercosis, cytomegalovirus infection, dengue fever, Desmodesmusinfection, deintamoebiasis, diphtheria, diphyllobothriasis,dracunculiasis, ebola hemorrhagic fever, echinococcosis, ehrlichiosis,enterobiasis, Enterococcus infection, Enterovirus infection, epidemictyphus, erythema infection, exanthema subitum, fasciolopsiasis,fasciolosis, fatal familial insomnia, filariasis, food poisoning byClostridium myonecrosis, free-living amebic infection, Fusobacteriuminfection, gas gangrene, geotrichosis, Gerstmann-Sträussler-Scheinkersyndrome, giardiasis, glanders, gnathostomiasis, gonorrhea, granulomainguinale, Group A streptococcal infection, Group B streptococcalinfection, Haemophilus influenzae infection, hand foot and mouthdisease, hantavirus pulmonary syndrome, Heartland virus disease,Heliobacter pylori infection, hemolytic-uremic syndrome, hemorrhagicfever with renal syndrome, hepatitis A, hepatitis B, hepatitis C,hepatitis D, hepatitis E, herpes simplex, histoplasmosis, hookworminfection, human bocavirus infection, human ewingii ehrlichiosis, humangranulocyte anaplasmosis, human metapneuomovirus infection, humanmonocytic ehrlichiosis, human papillomavirus infection, humanparainfluenza virus infection, hymenolepiasis, Epstein-Barr virusinfectious mononucleosis, influenza, isosporiasis, Kawasaki disease,keratitis, Kingella kingae infection, kuru, lassa fever, Legionnaires'disease, Pontiac fever, leishmaniasis, leprosy, leptospirosis,listeriosis, lyme disease, lymphatic filariasis, lymphocyticchoriomeningitis, malaria, Marburg hemorrhagic fever, measles, MiddleEast respiratory syndrome, melioidosis, meningitis, meningococcaldisease, metagonimiasis, microsporidiosis, molluscum contagiosum,monkeypox, mumps, murine typhus, mycoplasma pneumonia, mycetoma,myiasis, neonatal conjunctivitis, variant Creutzfeldt-Jakob disease,nocardiosis, onchocerciasis, paracoccidioidomycosis, paragonimiasis,pasteurellosis, pediculosis capitis, pediculosis corporis, pediculosispubis, pelvic inflammatory disease, pertussis, plague, pneumonia,poliomyelitis, Prevotella infection, primary amoebicmeningoencephalitis, progressive multifocal leukoencephalopathy,psittacosis, Q fever, rabies, relapsing fever, respiratory syncytialvirus infection, rhinosporidiosis, rhinovirus infection, rickettsialinfection, rickettsialpox, Rift Valley Fever, Rocky Mountain spottedfever, rotavirus infection, rubella, salmonellosis, severe acuterespiratory syndrome, scabies, schistosomiasis, sepsis, shigellosis,shingles, smallpox, sporothrichosis, staphylococcal food poisoning,staphylococcal infection, staphylococcal infection, strongyloidiasis,subacute sclerosing panencephalitis, syphilis, taeniasis, tetanus, tineabarabe, tinea capitis, tinea corporis, tinea cruris, tinea manum, tineanigra, tinea pedis, tinea unguium, tinea versicolor, toxocariasis,trachoma, toxoplasmosis, trichinosis, trichomoniasis, trichuriasis,tuberculosis, tularemia, typhoid fever, Ureaplasma urealyticuminfection, valley fever, Venezuelan hemorrhagic fever, viral pneumonia,West Nile fever, white piedra, Yersinia psuedotuberculosis infection,yersiniosis, yellow fever, and zygomycosis.

Methods for diagnosing a subject as having an infectious disease, oridentifying a subject as having an infectious disease are well known inthe art. For example, a medical professional (e.g., a physician, aphysician's assistant, or a technician) can diagnose infectious diseasein a subject by observing one or more symptoms of infectious disease ina subject. Non-limiting examples of symptoms of infectious diseaseinclude: fever, diarrhea, fatigue, and muscle aches. Methods ofdiagnosing a mammal as having an infectious disease or identifying asubject as having an infectious disease can further include performingone or more diagnostic tests (e.g., performing one or more diagnostictests on a biopsy or a blood sample). Diagnostic tests for diagnosing asubject as having an infectious disease or identifying a subject ashaving an infectious disease are known in the art.

Combination Therapy

This disclosure contemplates both monotherapy regimens as well ascombination therapy regimens.

In some embodiments, the methods described herein can further includeadministering one or more additional therapies (e.g., one or moreadditional therapeutic agents and/or one or more therapeutic regimens)in combination with administration of the compounds described herein.

In certain embodiments, the methods described herein can further includeadministering one or more additional cancer therapies.

The one or more additional cancer therapies can include, withoutlimitation, surgery, radiotherapy, chemotherapy, toxin therapy,immunotherapy, cryotherapy, cancer vaccines (e.g., HPV vaccine,hepatitis B vaccine, Oncophage, Provenge) and gene therapy, as well ascombinations thereof. Immunotherapy, including, without limitation,adoptive cell therapy, the derivation of stem cells and/or dendriticcells, blood transfusions, lavages, and/or other treatments, including,without limitation, freezing a tumor.

In some embodiments, the one or more additional cancer therapies ischemotherapy, which can include administering one or more additionalchemotherapeutic agents.

In certain embodiments, the additional cancer therapy comprises(chemotherapeutic agent) an immunomodulatory moiety, e.g., an immunecheckpoint inhibitor. In certain of these embodiments, the immunecheckpoint inhibitor targets an immune checkpoint receptor selected fromCTLA-4, PD-1, PD-L1, PD-1-PD-L1, PD-1-PD-L2, T cell immunoglobulin andmucin 3 (TIM3 or HAVCR2), Galectin 9-TIM3, Phosphatidylserine-TIM3,lymphocyte activation gene 3 protein (LAG3), MHC class II-LAG3,4-1BB-4-1BB ligand, OX40-OX40 ligand, GITR, GITR ligand-GITR, CD27,CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40-CD40 ligand,HVEM-LIGHT-LTA, HVEM, HVEM-BTLA, HVEM-CD160, HVEM-LIGHT,HVEM-BTLA-CD160, CD80, CD80-PDL-1, PDL2-CD80, CD244, CD48-CD244, CD244,ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2-TMIGD2,Butyrophilins, including BTNL2, Siglec family, TIGIT and PVR familymembers, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244,CD28, CD86-CD28, CD86-CTLA, CD80-CD28, Phosphatidylserine, TIM3,Phosphatidylserine-TIM3, SIRPA-CD47, VEGF, Neuropilin, CD160, CD30, andCD155 (e.g., CTLA-4 or PD1 or PD-L1) and other immunomodulatory agents,such as interleukin-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL-10,transforming growth factor-β (TGFβ), CD39, CD73 Adenosine-CD39-CD73, andCXCR4-CXCL12. See, e.g., Postow, M. J. Clin. Oncol. 33, 1 (2015).

In certain embodiments, the immune checkpoint inhibitor targets animmune checkpoint receptor selected from CTLA-4, PD-1, PD-L1,PD-1-PD-L1, and PD-1-PD-L2.

In certain embodiments, the immune checkpoint inhibitor is selectedfrom: nivolumab (also known as “OPDIVO”; formerly designated 5C4,BMS-936558, MDX-1106, or ONO-4538), pembrolizumab (also known as“KEYTRUDA”, lambrolizumab, and MK-3475. See WO 2008/156712), PDR001(Novartis; see WO 2015/112900), MEDI-0680 (AstraZeneca; AMP-514; see WO2012/145493), cemiplimab (REGN-2810) (Regeneron; see WO 2015/112800),JS001 (TAIZHOU JUNSHI PHARMA; see Si-Yang Liu et al., J. Hematol. Oncol.10:136 (2017)), BGB-A317 (Beigene; see WO 2015/35606 and US2015/0079109), INCSHRI210 (SHR-1210; Jiangsu Hengrui Medicine; see WO2015/085847; Si-Yang Liu et al., J. Hematol. Oncol. 10:136 (2017)),TSR-042 (ANB011; Tesaro Biopharmaceutical; see WO2014/179664), GLS-010(WBP3055; Wuxi/Harbin Gloria Pharmaceuticals; see Si-Yang Liu et al., J.Hematol. Oncol. 10:136 (2017)), AM-0001 (Armo), STI-1110 (SorrentoTherapeutics; see WO 2014/194302), AGEN2034 (Agenus; see WO2017/040790), MGD013 (Macrogenics); IBI308 (Innovent; see WO2017/024465, WO 2017/025016, WO 2017/132825, WO2017/133540); BMS-936559(formerly 12A4 or MDX-1105; see, e.g., U.S. Pat. No. 7,943,743 and WO2013/173223), MPDL3280A (also known as RG7446, atezolizumab, andTECENTRIQ; U.S. Pat. No. 8,217,149; see, also, Herbst et al. (2013) JClin Oncol 31(suppl):3000), durvalumab (IMFINZI; MEDI-4736; AstraZeneca;see WO 2011/066389), avelumab (Pfizer; MSB-0010718C; BAVENCIO; see WO2013/079174), STI-1014 (Sorrento; see WO2013/181634), CX-072 (Cytomx;see WO2016/149201), KN035 (3D Med/Alphamab; see Zhang et al., CellDiscov. 7:3 (March 2017), LY3300054 (Eli Lilly Co.; see, e.g, WO2017/034916), CK-301 (Checkpoint Therapeutics; see Gorelik et al., AACR:Abstract 4606 (April 2016)); urelumab, PF-05082566, MEDI6469, TRX518,varlilumab, CP-870893, BMS-986016, MGA271, lirilumab, IPH2201,emactuzumab, INCB024360, galunisertib, ulocuplumab, BKT140, Bavituximab,CC-90002, bevacizumab, MNRP1685A, ipilimumab (YERVOY; U.S. Pat. No.6,984,720), MK-1308 (Merck), AGEN-1884 (Agenus Inc.; WO 2016/196237),and tremelimumab (formerly ticilimumab, CP-675,206; AstraZeneca; see,e.g., WO 2000/037504 and Ribas, Update Cancer Ther. 2(3): 133-39(2007)).

In certain embodiments, the immune checkpoint inhibitor is selectedfrom: nivolumab, pembrolizumab, JS001, BGB-A317, INCSHR1210, TSR-042,GLS-010, STI-1110, MGD013, IBI308, BMS-936559, atezolizumab, durvalumab,avelumab, STI-1014, CX-072, KN035, LY3300054, CK-301, urelumab,PF-05082566, MEDI6469, TRX518, varlilumab, BMS-986016, ipilimumab,AGEN-1884, and tremelimumab.

In certain of these embodiments, the immune checkpoint inhibitor isselected from: Urelumab, PF-05082566, MEDI6469, TRX518, Varlilumab,CP-870893, Pembrolizumab (PD1), Nivolumab (PD1), Atezolizumab (formerlyMPDL3280A) (PDL1), MEDI4736 (PD-L1), Avelumab (PD-L1), PDR001 (PD1),BMS-986016, MGA271, Lirilumab, IPH2201, Emactuzumab, INCB024360,Galunisertib, Ulocuplumab, BKT140, Bavituximab, CC-90002, bevacizumab,and MNRP1685A.

In certain embodiments, the immune checkpoint inhibitor is selectedfrom: nivolumab, ipilimumab, pembrolizumab, atezolizumab, durvalumab andavelumab.

In certain embodiments, the immune checkpoint inhibitor is selectedfrom: nivolumab and ipilimumab.

In certain embodiments, the additional anti-cancer agent(chemotherapeutic agent) is a STING agonist. For example, the STINGagonist can include cyclic di-nucleotides, such as cAMP, cGMP, and cGAMPas well as modified cyclic di-nucleotides that include one or more ofthe following modification features (2′-O/3′-O linkage, phosphorothioatelinkage, adenine and/or guanine analogue, 2′-OH modification (e.g.,—OCH₃ or replacement, e.g., —F or N₃). See, e.g., WO 2014/189805.

In certain embodiments, the additional chemotherapeutic agent is analkylating agent. Alkylating agents are so named because of theirability to alkylate many nucleophilic functional groups under conditionspresent in cells, including, but not limited to cancer cells. In afurther embodiment, an alkylating agent includes, but is not limited to,Cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil,ifosfamide and/or oxaliplatin. In an embodiment, alkylating agents canfunction by impairing cell function by forming covalent bonds with theamino, carboxyl, sulfhydryl, and phosphate groups in biologicallyimportant molecules or they can work by modifying a cell's DNA. In afurther embodiment an alkylating agent is a synthetic, semisynthetic orderivative.

In certain embodiments, the additional chemotherapeutic agent is ananti-metabolite. Anti-metabolites masquerade as purines or pyrimidines,the building-blocks of DNA and in general, prevent these substances frombecoming incorporated in to DNA during the “S” phase (of the cellcycle), stopping normal development and division. Anti-metabolites canalso affect RNA synthesis. In an embodiment, an antimetabolite includes,but is not limited to azathioprine and/or mercaptopurine. In a furtherembodiment an anti-metabolite is a synthetic, semisynthetic orderivative.

In certain embodiments, the additional chemotherapeutic agent is a plantalkaloid and/or terpenoid. These alkaloids are derived from plants andblock cell division by, in general, preventing microtubule function. Inan embodiment, a plant alkaloid and/or terpenoid is a vinca alkaloid, apodophyllotoxin and/or a taxane. Vinca alkaloids, in general, bind tospecific sites on tubulin, inhibiting the assembly of tubulin intomicrotubules, generally during the M phase of the cell cycle. In anembodiment, a vinca alkaloid is derived, without limitation, from theMadagascar periwinkle, Catharanthus roseus (formerly known as Vincarosea). In an embodiment, a vinca alkaloid includes, without limitation,Vincristine, Vinblastine, Vinorelbine and/or Vindesine. In anembodiment, a taxane includes, but is not limited, to Taxol, Paclitaxeland/or Docetaxel. In a further embodiment a plant alkaloid or terpemoidis a synthetic, semisynthetic or derivative. In a further embodiment, apodophyllotoxin is, without limitation, an etoposide and/or teniposide.In an embodiment, a taxane is, without limitation, docetaxel and/orortataxel. In an embodiment, a cancer therapeutic is a topoisomerase.Topoisomerases are essential enzymes that maintain the topology of DNA.Inhibition of type I or type II topoisomerases interferes with bothtranscription and replication of DNA by upsetting proper DNAsupercoiling. In a further embodiment, a topoisomerase is, withoutlimitation, a type I topoisomerase inhibitor or a type II topoisomeraseinhibitor. In an embodiment a type I topoisomerase inhibitor is, withoutlimitation, a camptothecin. In another embodiment, a camptothecin is,without limitation, exatecan, irinotecan, lurtotecan, topotecan, BNP1350, CKD 602, DB 67 (AR67) and/or ST 1481. In an embodiment, a type IItopoisomerase inhibitor is, without limitation, epipodophyllotoxin. In afurther embodiment an epipodophyllotoxin is, without limitation, anamsacrine, etoposid, etoposide phosphate and/or teniposide. In a furtherembodiment a topoisomerase is a synthetic, semisynthetic or derivative,including those found in nature such as, without limitation,epipodophyllotoxins, substances naturally occurring in the root ofAmerican Mayapple (Podophyllum peltatum).

In certain embodiments, the additional chemotherapeutic agent is astilbenoid. In a further embodiment, a stilbenoid includes, but is notlimited to, Resveratrol, Piceatannol, Pinosylvin, Pterostilbene,Alpha-Viniferin, Ampelopsin A, Ampelopsin E, Diptoindonesin C,Diptoindonesin F, Epsilon-Vinferin, Flexuosol A, Gnetin H, HemsleyanolD, Hopeaphenol, Trans-Diptoindonesin B, Astringin, Piceid andDiptoindonesin A. In a further embodiment a stilbenoid is a synthetic,semisynthetic or derivative.

In certain embodiments, the additional chemotherapeutic agent is acytotoxic antibiotic. In an embodiment, a cytotoxic antibiotic is,without limitation, an actinomycin, an anthracenedione, ananthracycline, thalidomide, dichloroacetic acid, nicotinic acid,2-deoxyglucose and/or chlofazimine. In an embodiment, an actinomycin is,without limitation, actinomycin D, bacitracin, colistin (polymyxin E)and/or polymyxin B. In another embodiment, an antracenedione is, withoutlimitation, mitoxantrone and/or pixantrone. In a further embodiment, ananthracycline is, without limitation, bleomycin, doxorubicin(Adriamycin), daunorubicin (daunomycin), epirubicin, idarubicin,mitomycin, plicamycin and/or valrubicin. In a further embodiment acytotoxic antibiotic is a synthetic, semisynthetic or derivative.

In certain embodiments, the additional chemotherapeutic agent isselected from endostatin, angiogenin, angiostatin, chemokines,angioarrestin, angiostatin (plasminogen fragment), basement-membranecollagen-derived anti-angiogenic factors (tumstatin, canstatin, orarrestin), anti-angiogenic antithrombin III, signal transductioninhibitors, cartilage-derived inhibitor (CDI), CD59 complement fragment,fibronectin fragment, gro-beta, heparinases, heparin hexasaccharidefragment, human chorionic gonadotropin (hCG), interferonalpha/beta/gamma, interferon inducible protein (IP-10), interleukin-12,kringle 5 (plasminogen fragment), metalloproteinase inhibitors (TIMPs),2-methoxyestradiol, placental ribonuclease inhibitor, plasminogenactivator inhibitor, platelet factor-4 (PF4), prolactin 16 kD fragment,proliferin-related protein (PRP), various retinoids,tetrahydrocortisol-S, thrombospondin-1 (TSP-1), transforming growthfactor-beta (TGF-0), vasculostatin, vasostatin (calreticulin fragment)and the like.

In certain embodiments, the additional chemotherapeutic agent isselected from abiraterone acetate, altretamine, anhydrovinblastine,auristatin, bexarotene, bicalutamide, BMS 184476,2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzene sulfonamide,bleomycin,N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-proly-1-Lproline-t-butylamide,cachectin, cemadotin, chlorambucil, cyclophosphamide,3′,4′-didehydro-4′-deoxy-8′-norvin-caleukoblastine, docetaxol,doxetaxel, cyclophosphamide, carboplatin, carmustine, cisplatin,cryptophycin, cyclophosphamide, cytarabine, dacarbazine (DTIC),dactinomycin, daunorubicin, decitabine dolastatin, doxorubicin(adriamycin), etoposide, 5-fluorouracil, finasteride, flutamide,hydroxyurea and hydroxyureataxanes, ifosfamide, liarozole, lonidamine,lomustine (CCNU), MDV3100, mechlorethamine (nitrogen mustard),melphalan, mivobulin isethionate, rhizoxin, sertenef, streptozocin,mitomycin, methotrexate, taxanes, nilutamide, onapristone, paclitaxel,prednimustine, procarbazine, RPR109881, stramustine phosphate,tamoxifen, tasonermin, taxol, tretinoin, vinblastine, vincristine,vindesine sulfate, and vinflunine.

In certain embodiments, the additional chemotherapeutic agent isplatinum, cisplatin, carboplatin, oxaliplatin, mechlorethamine,cyclophosphamide, chlorambucil, azathioprine, mercaptopurine,vincristine, vinblastine, vinorelbine, vindesine, etoposide andteniposide, paclitaxel, docetaxel, irinotecan, topotecan, amsacrine,etoposide, etoposide phosphate, teniposide, 5-fluorouracil, leucovorin,methotrexate, gemcitabine, taxane, leucovorin, mitomycin C,tegafur-uracil, idarubicin, fludarabine, mitoxantrone, ifosfamide anddoxorubicin. Additional agents include inhibitors of mTOR (mammaliantarget of rapamycin), including but not limited to rapamycin,everolimus, temsirolimus and deforolimus.

In still other embodiments, the additional chemotherapeutic agent can beselected from those delineated in U.S. Pat. No. 7,927,613.

In yet another embodiment, the methods can further include administeringone or both of: (i) one or more anti-fungal agents (e.g., selected fromthe group of bifonazole, butoconazole, clotrimazole, econazole,ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole,sertaconazole, sulconazole, tioconazole, albaconazole, efinaconazole,epoziconazole, fluconazole, isavuconazole, itraconazole, posaconazole,propiconazole, ravusconazole, terconazole, voriconazole, abafungin,amorolfin, butenafine, naftifine, terbinafine, anidulafungin,caspofungin, micafungin, benzoic acid, ciclopirox, flucytosine,5-fluorocytosine, griseofulvin, haloprogin, tolnaflate, undecylenicacid, and balsam of peru) and (ii) one or more antibiotics (e.g.,selected from the group of amikacin, gentamicin, kanamycin, neomycin,netilmicin, tobramycin, paromomycin, streptomycin, spectinomycin,geldanamycin, herbimycin, rifaximin, loracarbef, ertapenem, doripenem,imipenem, cilastatin, meropenem, cefadroxil, cefazolin, cefalotin,cefalothin, cefalexin, cefaclor, cefamandole, cefoxitin, cefprozil,cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime,cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone,cefepime, ceftaroline fosamil, ceftobiprole, teicoplanin, vancomycin,telavancin, dalbavancin, oritavancin, clindamycin, lincomycin,daptomycin, azithromycin, clarithromycin, dirithromycin, erythromycin,roxithromycin, troleandomycin, telithromycin, spiramycin, aztreonam,furazolidone, nitrofurantoin, linezolid, posizolid, radezolid,torezolid, amoxicillin, ampicillin, azlocillin, carbenicillin,cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin,nafcillin, oxacillin, penicillin G, penicillin V, piperacillin,penicillin G, temocillin, ticarcillin, amoxicillin, calvulanate,ampicillin, subbactam, piperacillin, tazobactam, ticarcillin,clavulanate, bacitracin, colistin, polymyxin B, ciprofloxacin, enoxacin,gatifloxacin, gemifloxacin, levofloxacin, lomefloxacin, moxifloxacin,nalidixic acid, norfloxacin, ofloxacin, trovafloxacin, grepafloxacin,sparfloxacin, temafloxacin, mafenide, sulfacetamide, sulfadiazine,silver sulfadiazine, sulfadimethoxine, sulfamethoxazole, sulfanilimide,sulfasalazine, sulfisoxazole, trimethoprim-sulfamethoxazole,sulfonamideochrysoidine, demeclocycline, minocycline, oytetracycline,tetracycline, clofazimine, dapsone, dapreomycin, cycloserine,ethambutol, ethionamide, isoniazid, pyrazinamide, rifampicin, rifabutin,rifapentine, streptomycin, arsphenamine, chloramphenicol, fosfomycin,fusidic acid, metronidazole, mupirocin, platensimycin, quinupristin,dalopristin, thiamphenicol, tigecycyline, tinidazole, trimethoprim, andteixobactin).

In certain embodiments, the second therapeutic agent or regimen isadministered to the subject prior to contacting with or administeringthe chemical entity (e.g., about one hour prior, or about 6 hours prior,or about 12 hours prior, or about 24 hours prior, or about 48 hoursprior, or about 1 week prior, or about 1 month prior).

In other embodiments, the second therapeutic agent or regimen isadministered to the subject at about the same time as contacting with oradministering the chemical entity. By way of example, the secondtherapeutic agent or regimen and the chemical entity are provided to thesubject simultaneously in the same dosage form. As another example, thesecond therapeutic agent or regimen and the chemical entity are providedto the subject concurrently in separate dosage forms.

In still other embodiments, the second therapeutic agent or regimen isadministered to the subject after contacting with or administering thechemical entity (e.g., about one hour after, or about 6 hours after, orabout 12 hours after, or about 24 hours after, or about 48 hours after,or about 1 week after, or about 1 month after).

Patient Selection

In some embodiments, the methods described herein further include thestep of identifying a subject (e.g., a patient) in need of suchtreatment (e.g., by way of biopsy, endoscopy, or other conventionalmethod known in the art). In certain embodiments, the NLRP3 protein canserve as a biomarker for certain types of cancer.

In some embodiments, the chemical entities, methods, and compositionsdescribed herein can be administered to certain treatment-resistantpatient populations (e.g., patients resistant to checkpoint inhibitors).

In some embodiments, the compounds of the present invention may be usedin therapy. In certain embodiments, the present invention provides acombined preparation of a compound of the present invention, or apharmaceutically acceptable salt thereof, and additional therapeuticagent(s) for simultaneous, separate or sequential use in therapy.

In some embodiments, a compound of the present invention, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition containing the same, may be used as a medicament. In certainembodiments, the compounds of the invention may be used for themanufacture of a medicament for the treatment of cancer.

EXAMPLES

As can be appreciated by the skilled artisan, methods of synthesizingthe compounds of the formulae herein will be evident to those ofordinary skill in the art. For example, the compounds described hereincan be synthesized, e.g., using one or more of the methods describedherein and/or using methods described in, e.g., US 2015/0056224.Synthetic chemistry transformations and protecting group methodologies(protection and deprotection) useful in synthesizing the compoundsdescribed herein are known in the art and include, for example, thosesuch as described in R. Larock, Comprehensive Organic Transformations,VCH Publishers (1989); T. W. Greene and RGM. Wuts, Protective Groups inOrganic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M.Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wileyand Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents forOrganic Synthesis, John Wiley and Sons (1995), and subsequent editionsthereof. The starting materials used in preparing the compounds of theinvention are known, made by known methods, or are commerciallyavailable. The skilled artisan will also recognize that conditions andreagents described herein that can be interchanged with alternativeart-recognized equivalents. For example, in many reactions,triethylamine can be interchanged with other bases, such asnon-nucleophilic bases (e.g. diisopropylamine,1,8-diazabicycloundec-7-ene, 2,6-di-tert-butylpyridine, ortetrabutylphosphazene).

The skilled artisan will recognize a variety of analytical methods thatcan be used to characterize the compounds described herein, including,for example, ¹H NMR, heteronuclear NMR, mass spectrometry, liquidchromatography, and infrared spectroscopy. The foregoing list is asubset of characterization methods available to a skilled artisan and isnot intended to be limiting.

To further illustrate the foregoing, the following non-limiting,exemplary synthetic schemes are included. Variations of these exampleswithin the scope of the claims are within the purview of one skilled inthe art and are considered to fall within the scope of the invention asdescribed, and claimed herein. The reader will recognize that theskilled artisan, provided with the present disclosure, and skill in theart is able to prepare and use the invention without exhaustiveexamples.

The following abbreviations have the indicated meanings:

-   -   ACN=acetonitrile    -   CH₂Cl₂=dichloromethane    -   CH₃ReO₃=methyltrioxorhenium    -   Cs₂CO₃=cesium carbonate    -   d=doublet    -   DCM=dichloromethane    -   DIEA=N,N-diethylisopropylamine    -   DMF=N,N-dimethylformamide    -   DMSO=dimethylsulfoxide    -   ES=electrospray ionization    -   EA, EtOAc=ethyl acetate    -   EtOH=ethanol    -   equiv=equivalents    -   g=grams    -   h=hours    -   HCl=hydrogen chloride (usually as a solution)    -   H₂O=water    -   H₂O₂=hydrogen peroxide    -   HATU=1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium        3-oxide hexafluorophosphate    -   HPLC=high-performance liquid chromatography    -   K₂CO₃=potassium carbonate    -   LC/MS=liquid chromatography mass spectrometer    -   LiBH₄=lithium borohydride    -   m=multiplet    -   M=molar    -   m-CPBA=meta-chloroperoxybenzoic acid    -   mg=milligram(s)    -   MeOH=methanol    -   MHz=megahertz    -   mL=milliliter(s)    -   mmol=millimole(s)    -   NaHCO₃=sodium hydrogen carbonate    -   Na₂CO₃=sodium carbonate    -   NaOH=sodium hydroxide    -   Na₂SO₄=sodium sulfate    -   NEt₃=trimethylamine    -   NH₃=ammonia    -   NH₄OH or NH₃H₂O=ammonium hydroxide    -   NH₄HCO₃=ammonium hydrogen carbonate    -   nm=nanometer    -   PdCl₂(PPh₃)₂=bis(triphenylphosphine)palladium (II) dichloride    -   Pd(dppf)Cl₂=[1,1′-Bis(diphenylphosphino)ferrocene]        dichloropalladium (II)    -   PE=petroleum ether    -   PMB=para-methoxybenzyl    -   POCl₃=phosphorous oxychloride    -   ppm=parts per million    -   Py=pyridine    -   s=singlet    -   t=triplet    -   T₃P=2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide    -   TFA=trifluoroacetic acid    -   TLC=thin layer chromatography    -   TsCl=para-toluenesulfonyl chloride    -   ° C.=degrees Celsius    -   pmol=micromolar

Generic Procedure for the Synthesis of Compounds of Formula I

The compounds of the present invention can be prepared in a number ofways well known to one skilled in the art of organic synthesis. Thecompounds of the present invention can be synthesized using the methodsdescribed below, together with synthetic methods known in the art ofsynthetic organic chemistry, or variations thereon as appreciated bythose skilled in the art. Preferred methods include, but are not limitedto, those described below.

The compounds of this invention may be prepared using the reactions andtechniques described in this section. The reactions are performed insolvents appropriate to the reagents and materials employed and aresuitable for the transformations being effected. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including choice ofsolvent, reaction atmosphere, reaction temperature, duration of theexperiment and work up procedures, are chosen to be the conditionsstandard for that reaction, which should be readily recognized by oneskilled in the art. It is understood by one skilled in the art oforganic synthesis that the functionality present on various portions ofthe molecule must be compatible with the reagents and reactionsproposed. Such restrictions to the substituents that are compatible withthe reaction conditions will be readily apparent to one skilled in theart and alternate methods must then be used. This will sometimes requirea judgment to modify the order of the synthetic steps or to select oneparticular process scheme over another in order to obtain a desiredcompound of the invention. It will also be recognized that another majorconsideration in the planning of any synthetic route in this field isthe judicious choice of the protecting group used for protection of thereactive functional groups present in the compounds described in thisinvention. An authoritative account describing the many alternatives tothe trained practitioner is Greene and Wuts (Protective Groups InOrganic Synthesis, Third Edition, Wiley and Sons, 1999).

Compounds of Formula (I) may be prepared by reference to the methodsillustrated in the following Schemes. As shown therein the end productis a compound having the structural formula as Formula (I). It will beunderstood that any compound of Formula (I) may be produced by theschemes by the suitable selection of reagents with appropriatesubstitution. Solvents, temperatures, pressures, and other reactionconditions may readily be selected by one of ordinary skill in the art.Starting materials are commercially available or readily prepared by oneof ordinary skill in the art. Constituents of compounds are as definedherein or elsewhere in the specification. The synthesis of the compoundsof Formula (I) can be made using the methods summarized in Scheme 1.

Step 1: The first step of Scheme 1 begins with a suitably functionalizedquinolinol (i). If desired, the groups R⁸ and R⁹ may be the groups R⁴and R⁵ found in the final product (xii). Alternatively, one or both ofR⁸ and R⁹ may be groups that can be modified at a later stage of thesynthesis, such as bromo. The first step of Scheme 1 may be accomplishedby treating compound (i) with a suitable nitrating agent, such as nitricacid, in a suitable solvent, such as propionic acid, at an appropriatetemperature, such as 130° C., to give compound (ii).Step 2: The second step of Scheme 1 may be accomplished by treatingcompound (ii) with a suitable chlorinating agent, such as phosphorousoxychloride, at an appropriate temperature, such as 120° C., to givecompound (iii).Step 3: In the third step of Scheme 1, the group R¹⁰ installed may bethe desired group R³ found in the final product (xii). Alternatively, aprotecting group such as p-methoxybenzyl may be installed and removed ata later stage of the synthesis. Step 3 may be accomplished by treatingcompound (iii) with a suitable amine, such as p-methoxybenzylamine, andbase, such as triethylamine, in a solvent such as dichloromethane at asuitable temperature, such as room temperature, to give compound (iv).Step 4: The fourth step of Scheme 1 may be accomplished by treatingcompound (iv) with a suitable reducing agent, such as tin(II) chloride,in a solvent such as ethanol, at an appropriate temperature, such as 65°C., to give compound (v).Step 5: In the fifth step of Scheme 1, the groups R¹¹ and R¹² installedmay be the groups R¹ and R² desired in the final product (xii).Alternatively, they may be groups that allow the installation of R¹and/or R² in a later step, such as a Boc protecting group. Step 5 may beaccomplished by treating compound (v) with a suitably functionalizedcarboxylic acid, such as N-Boc-N-ethyl glycine, a suitable couplingagent, such as HATU, and a suitable amine, such as triethylamine, in asolvent such as dichloromethane at an appropriate temperature, such asroom temperature, to give compound (vi).Step 6: The sixth step of Scheme 1 may be accomplished by treatingcompound (vi) with a suitable base, such as triethylamine, in a solventsuch as ethanol at an appropriate temperature, such as 70° C., to givecompound (vii).Step 7: The seventh step of Scheme 1 may be accomplished by treatingcompound (vii) with a suitable oxidant, such as m-CPBA, in a solventsuch as dichloromethane to give compound (viii).Step 8: The eighth step of Scheme 1 may be accomplished by treatingcompound (viii) with a reagent, such as tosyl chloride, and an amine,such as ammonia, in a solvent such as dichloromethane to give compound(ix).Steps 9, 10, and 11 of Scheme 1 may optionally be conducted to transformone or more of the groups R⁸, R⁹, R¹⁰, R¹¹, and R¹² into the groups R¹,R², R³, R⁴, and R⁵ desired in the final product (xii). An individualskilled in the art will recognize that one or more of these steps maynot be necessary, depending on the reagents selected earlier in thesynthesis and final product desired. Furthermore, an individual skilledin the art will recognize that these steps may be conducted in analternative order, depending on the final product desired.Step 9: The ninth step of Scheme 1 may optionally be conducted totransform one or both of the groups R⁸ and R⁹ into the groups R⁴ and R⁵desired in the final product. For example, if R⁹ is bromo, and thedesired R⁵ is 3-pyrazoyl, this transformation may be accomplished bytreating compound (ix) with a suitable boronic ester, such as3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, in the presence ofa catalyst such as Pd(dppf)Cl₂ dichloromethane complex, and a base suchas cesium carbonate in a solvent mixture such as dioxane/water at asuitable temperature, such as 100° C., to give compound (x).Alternatively, if R⁹ is bromo, and the desired R⁵ is 1-pyrazolyl, thisstep may be accomplished by treating compound (ix) with pyrazole in thepresence of a catalyst, such as copper(I) iodide, a ligand, such asN,N′-dimethyl-ethylenediamine, and a base, such as sodium carbonate, ina solvent such as dimethylsulfoxide at an appropriate temperature, suchas 120° C., to give compound (x).Step 10: The tenth step of Scheme 1 may optionally be conducted totransform one or both of the groups R¹¹ and R¹² into the groups R¹ andR² desired in the final product. If one or both of the groups R¹¹ andR¹² is a protecting group such as Boc, this group may be removed undersuitable conditions, such as by treating compound (x) with HCl indioxane. If R¹¹ and/or R¹² is H, and the desired R¹¹ and/or R¹² is anamide, this step may be accomplished by treating compound (x) with asuitable anhydride and base, such as acetic anhydride and triethylamine,in a solvent such as dichloromethane, or by treating compound (x) with asuitable acid, coupling agent, and base, such as3-hydroxy-3-methylbutanoic acid,2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide, andHunig's base in a solvent such as DMF, to give compound (xi).Alternatively, If R¹¹ and/or R¹² is H, and the desired R¹ and/or R² isan amine, this step may be accomplished by treating compound (x) with anappropriate aldehyde or ketone, such as isobutyraldehyde, and reducingagent, such as sodium triacetoxyborohydride, in a solvent such asmethanol to give compound (xi). Alternatively, if R¹¹ and/or R¹² is H,and the desired R¹ and/or R² is a carbamate, this step may beaccomplished by treating compound (x) with an approriate chloroformate,such as ethyl chloroformate, and appropriate base, such astriethylamine, in a solvent such as dichloromethane, followed bytreatment with an appropriate base, such as triethylamine, in an alcoholsolvent, such as methanol, to give compound (xi). Alternatively, if Rnand/or R₁₂ is H, and the desired R₁ and/or R₂ is a urea, this step maybe accomplished by treating compound (x) with an appropriate carbamoylchloride, such as morpholine-4-carbonyl chloride, or an appropriateisocyante, such as ethyl isocyante, in the presence of a base such asHunig's base in a solvent such as DMF. Alternatively, if R¹¹ and/or R¹²is H, and the desired R¹ and/or R² is a sulfonylurea, this step may beaccomplished by treating compound (x) with an appropriate sulfamoylchloride, such as dimethylsulfamoyl chloride, and base, such as Hunig'sbase, in a solvent such as DMF to give compound (xi). Alternatively, ifR¹¹ and/or R¹² is H, and the desired R¹ and/or R² is a sulfonamide, thisstep may be accomplished by treating compound (x) with an appropriatesulfonyl chloride and base, such as 2-propylsulfonyl chloride andHunig's base, in a solvent such as DMF.Step 11: The eleventh step of Scheme 1 may optionally be conducted totransform the group R¹⁰ into the group R³ desired in the final product(xii). For example, if R₁₀ is a protecting group such asp-methoxybenzyl, it may be removed under appropriate conditions, such astreating with trifluoroacetic acid at suitable temperature, such as 70°C., to give compound (xii).

Example 1: Procedure for Synthesis of7-Bromo-N⁴-(4-methoxybenzyl)quinoline-3,4-diamine

Step 1. Preparation of 7-bromo-3-nitroquinolin-4-ol

7-bromoquinolin-4-ol (4.5 g, 20.0 mol) was dissolved in propionic acid(34 mL). The mixture was heated to 130° C., and nitric acid (1.7 mL,70%) was added. The reaction was heated at 130° C. (bath temperature)for 4 hours at which time it was cooled to room temperature andfiltered. The resulting solid was washed with water (3×20 mL),2-propanol (20 mL), and hexanes (20 mL). The product was then driedunder high vacuum to provide 3.8 g (70.6%) of7-bromo-3-nitroquinolin-4-ol as a tan powder, which was used in the nextstep without further purification. (ES, m/z): [M+H]+=269.2/271.3.

Step 2. Preparation of 7-bromo-4-chloro-3-nitroquinoline

7-Bromo-3-nitroquinolin-4-ol (3.8 g, 14.12 mmol) was suspended in POCl₃(20 mL). Anhydrous DMF (1 mL) was added. The mixture was then heated to120° C. under an atmosphere of nitrogen for 3 hours at which time thereaction was cooled to room temperature. The precipitate was collectedby filtration, washed with water, and then partitioned between CH₂Cl₂(60 mL) and a saturated aqueous solution of Na₂CO₃. The organic layerwas separated, washed with brine, dried over Na₂SO₄, filtered, andconcentrated to afford 3.3 g (11.5 mmol, 81%) of7-bromo-4-chloro-3-nitroquinoline as a beige-colored solid. (ES, m/z):[M+H]+=287.1/288.9.

-   -   Note: It was discovered that if higher temperatures and longer        reaction times are used, a significant amount of Cl—Br exchange        occurs which affords an intermediate that does not undergo        subsequent cross-coupling reactions.

Step 3. Preparation of7-bromo-N-(4-methoxybenzyl)-3-nitroquinolin-4-amine

7-bromo-4-chloro-3-nitroquinoline (1.9 g, 6.62 mmol) was dissolved inCH₂Cl₂ (20 mL). 4-methoxy benzylamine (0.85 mL, 6.7 mmol) was added,followed by NEt₃ (0.95 mL, 6.7 mmol). The mixture was stirred at roomtemperature for 4 h at which time it was diluted with CH₂Cl₂ (30 mL),washed with water, washed with brine, dried over Na₂SO₄, and filtered.The resulting solution was evaporated to dryness to afford(7-bromo-3-nitro-quinolin-4-yl)-(4-methoxy-benzyl)-amine as a yellowfoam (2.5 g, 6.44 mmol, 97%). This material was used in the next stepwithout further purification. (ES, m/z): [M+H]⁺=388.3/390.1.

Step 4. Preparation of 7-bromo-N⁴-(4-methoxybenzyl)quinoline-3,4-diamine

(7-Bromo-3-nitro-quinolin-4-yl)-(4-methoxy-benzyl)-amine (2.5 g, 6.44mmol) was dissolved in ethanol (60 mL) at room temperature. Tin (II)chloride hydrate (4.8 g, 21.2 mmol) was added in one portion. Themixture was stirred at 65° C. for 3 h at which time water (50 mL) wasadded, followed by a saturated aqueous solution of NaHCO₃ to pH ˜9. Themixture was extracted with EtOAc (3×60 mL), and the combined organiclayers were dried over Na₂SO₄, filtered, and concentrated to afford7-bromo-N⁴-(4-methoxy-benzyl)-quinoline-3,4-diamine (1.5 g, 4.2 mmol,65%). This material was used in the next step without furtherpurification. (ES, m/z): [M+H]+=357.9/360.1.

Example 2: Preparation Method of Analogs Wherein R¹/R²=Alkyl, Acetyl andR⁵=Aryl, Heteroaryl, Heterocyclyl, or Amino

Step 1. Preparation of tert-butyl((7-bromo-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-2-yl)methyl)(ethyl)carbamate

To a solution of 7-bromo-N⁴-(4-methoxy-benzyl)-quinoline-3,4-diamine(0.950 g, 2.65 mmol, Example 1) and(tert-butoxycarbonyl-ethyl-amino)-acetic acid (0.600 g, 2.92 mmol)) inCH₂Cl₂ (20 mL) was added HATU (1.1 g, 2.65 mmol) and NEt₃ (0.4 mL, 2.87mmol). The mixture was stirred at room temperature for 12 hours at whichtime it was then concentrated to remove all volatiles. EtOH (10 mL) wasadded, followed by NEt₃ (4 mL). The mixture was stirred in a 70° C. oilbath for 15 hours and then cooled to room temperature. Most of thevolatiles were evaporated in vacuo, and the resulting residue waspartitioned between CH₂Cl₂ (30 mL) and water (30 mL). The organic layerwas further washed with water (30 mL), brine, dried over Na₂SO₄,filtered, and concentrated. The crude tert-butyl((7-bromo-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-2-yl)methyl)(ethyl)carbamate(0.972 g, 1.85 mmol, 70% yield) was used in the next step withoutfurther purification. (ES, m/z): [M+H]⁺=525.1/527.4.

Step 2. Preparation ofN-((7-bromo-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-2-yl)methyl)-N-ethylacetamide

To a solution of tert-butyl((7-bromo-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-2-yl)methyl)(ethyl)carbamate(0.972 g, 1.85 mmol) in dioxane (10 mL) was added HCl (10 mL, 4 N indioxane). The mixture was stirred at room temperature for 4 hours atwhich time it was concentrated to remove all volatiles, then taken up inCH₂Cl₂ (20 mL). The mixture was stirred in an ice water bath for 5 min,then NEt₃ (0.4 mL, 2.88 mmol) and Ac₂O (0.25 mL, 2.64 mmol) were addedsequentially. The mixture was further stirred at room temperature for 30min and then diluted with water (20 mL). The layers were separated andthe organic layer was washed with water (20 mL), brine, dried overNa₂SO₄, filtered, and concentrated. The crudeN-((7-bromo-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-2-yl)methyl)-N-ethylacetamide(0.800 g, 1.71 mmol, 92% yield) was used in the next step withoutfurther purification. (ES, m/z): [M+H]⁺=467.2/469.4

Step 3. Preparation of7-bromo-2-((N-ethylacetamido)methyl)-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinoline5-oxide

To a solution ofN-((7-bromo-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-2-yl)methyl)-N-ethylacetamide(0.800 g, 1.71 mmol) in CH₂Cl₂ (20 mL) were added H₂O₂ (10 mL) andm-chloroperoxybenzoic acid (70% grade, 0.500 g, 0.2 mmol). The mixturewas stirred for 15 hours at room temperature at which time it wasdiluted with a saturated aqueous solution of NaHCO₃ and extracted withCH₂Cl₂ (3×20 mL). The combined organic layers were washed with brine,dried over Na₂SO₄, filtered, and concentrated to afford crude7-bromo-2-((N-ethylacetamido)methyl)-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinoline5-oxide (0.800 g, 1.65 mmol, 96% yield) as a brownish foam. (ES, m/z):[M+H]⁺=483.2/485.5.

Step 4. Preparation ofN-((4-amino-7-bromo-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-2-yl)methyl)-N-ethylacetamide

To a solution of7-bromo-2-((N-ethylacetamido)methyl)-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinoline5-oxide (0.800 g, 1.65 mmol) and NH₄OH (10 mL) in dichloromethane (20mL) cooled in an ice water bath, was added p-toluenesulfonyl chloride(0.439 g, 2.3 mmol) in CH₂Cl₂ (10 mL) dropwise. The resulting solutionwas stirred another 30 min after addition was complete. Water (20 mL)was added and the layers were separated. The aqueous layer was extractedwith CH₂Cl₂ (30 mL). The combined organic layers were filtered through apad of Na₂SO₄ and the filtrate was concentrated in vacuo. The residuewas triturated with EtOAc/hexanes (⅓) and dried under high vacuum toaffordN-((4-amino-7-bromo-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-2-yl)methyl)-N-ethylacetamideas a yellow solid (677 mg, 1.4 mmol, 85% yield). (ES, m/z):[M+H]⁺=482.3/484.2.

Step 5. Coupling with Aryl Bromide 5a. Preparation ofN-((4-amino-1-(4-methoxybenzyl)-7-(1H-pyrazol-1-yl)-1H-imidazo[4,5-c]quinolin-2-yl)methyl)-N-ethylacetamide(General Procedure for Ullman Coupling of N-heterocycles)

To a solution ofN-((4-amino-7-bromo-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-2-yl)methyl)-N-ethylacetamide(25 mg, 52 μmol) in dry DMSO (2 mL) was added the N-heterocycle (2equiv; pyrazole in the example above) followed by CuI (25 mg, 2 equiv)and Na₂CO₃ (30 mg, 4 equiv). The mixture was degassed,N,N′-dimethylethylenediamine (20 mg, 3 equiv) was added, and the mixturewas stirred at 120° C. for 2 h. The cooled mixture was diluted withEtOAc, filtered, and the solvent evaporated. The resulting crudeN-((4-amino-1-(4-methoxybenzyl)-7-(1H-pyrazol-1-yl)-1H-imidazo[4,5-c]quinolin-2-yl)methyl)-N-ethylacetamidewas used in the deprotection step without further purification.

or

5b. Alternative Preparation to Install Aryl Groups Instead ofN-Heterocycles: General Procedure for Suzuki Coupling of ArylboronicAcids and Esters

To a solution ofN-((4-amino-7-bromo-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-2-yl)methyl)-N-ethylacetamide(25 mg, 52 μmol) was added the aryl(heteroaryl)boronic acid (or arylboronate ester) (2 equiv), followed by Pd(dppf)Cl₂.CH₂Cl₂ (5 mg) and anaqueous solution of K₂CO₃ (1 mL, 2M aqueous). The mixture was heated ina Biotage Initiator microwave reactor at 120° C. for 10 min. The organiclayer was diluted with EtOAc and separated, and the aqueous layer waswashed with EtOAc. The combined organic phases were filtered, evaporatedand the product residue used in the next step without furtherpurification.

Step 6. General Deprotection Procedure—Preparation ofN-((4-amino-7-aryl(heteroaryl)-1H-imidazo[4,5-c]quinolin-2-yl)methyl)-N-ethylacetamide

The crude product from the previous step was dissolved in TFA (2 mL) andstirred at 70° C. for 1 h while monitoring the reaction progress byLC/MS. Once the PMB protecting group was completely cleaved as indicatedby LC/MS, the solvent was evaporated and the residue purified by HPLC toaffordN-((4-amino-7-aryl(heteroaryl)-1H-imidazo[4,5-c]quinolin-2-yl)methyl)-N-ethylacetamideas the trifluoroacetate salt.

The compounds depicted in Table 2 were made according to the abovesynthetic procedures.

TABLE 2 Compound NAME [M + H]+ 165N-[(4-amino-7-phenyl-1H-imidazo[4,5-c] 360.2quinolin-2-yl)methyl]-N-ethylacetamide 166N-[(4-amino-7-pyridin-3-yl-1H-imidazo[4,5-c] 361.2quinolin-2-yl)methyl]-N-ethylacetamide 167N-[(4-amino-7-pyridin-4-yl-1H-imidazo[4,5-c] 361.2quinolin-2-yl)methyl]-N-ethylacetamide 168N-[[4-amino-7-(2,5-dimethylpyrazol-3-yl)-1H- 378.2imidazo[4,5-c]quinolin-2-yl]methyl]-N- ethylacetamide 169N-[[4-amino-7-(1-propylpyrazol-4-yl)-1H-imidazo 392.2[4,5-c]quinolin-2-yl]methyl]-N-ethylacetamide 170N-[(4-amino-7-propan-2-yl-1H-imidazo[4,5-c] 326.2quinolin-2-yl)methyl]-N-ethylacetamide 171N-[(4-amino-7-ethyl-1H-imidazo[4,5-c] 312.2quinolin-2-yl)methyl]-N-ethylacetamide 172N-[(4-amino-7-propyl-1H-imidazo[4,5-c] 326.2quinolin-2-yl)methyl]-N-ethylacetamide 173N-[(4-amino-7-cyclopentyl-1H-imidazo[4,5-c] 352.2quinolin-2-yl)methyl]-N-ethylacetamide 175N-[[4-amino-7-(2-fluoropyridin-3-yl)-1H-imidazo 379.2[4,5-c]quinolin-2-yl]methyl]-N-ethylacetamide 177N-[(4-amino-7-bromo-1H-imidazo[4,5-c]) 362.1quinolin-2-yl)methyl]-N-ethylacetamide 179N-[(4-amino-7-chloro-1H-imidazo[4,5-c] 318.1quinolin-2-yl)methyl]-N-ethylacetamide 180N-[(4-amino-7-pyrazol-1-yl-1H-imidazo[4,5-c] 350.2quinolin-2-yl)methyl]-N-ethylacetamide 182N-[1-(4-amino-7-bromo-1H-imidazo[4,5-c] 376.1quinolin-2-yl)ethyl]-N-ethylacetamide

Example 3: Example Preparation Method of Analogs Wherein R¹=H, R²=Alkyl,and R⁵=Aryl, Heteroaryl, Heterocyclyl, or Amino

The following synthetic schemes was used to prepare compound 101 andrelated analogs, compounds 463, 465 and 468. Additional analogs of thesecompounds may be prepared by, for example, substituting the hydrogen ofthe secondary amino group of compound 101 with a range of additionalsubstituents, by means of, for example, acylation and sulfonylationusing transformations known to those of skill in the art, as describedin Example 4. The additional analogs made in this manner include, forexample, compounds 105, 109, 110, 112 (described in Example 4a), 114,118, 121, 123, 124, 125, 126, 133, 379, 383, 395, 406, 410, and 411.

Example 3a. Preparation of2-[(Ethylamino)methyl]-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-c]quinolin-4-aminehydrochloride (Compound 101)

Step 1. tert-ButylN-[[(4-amino-7-bromoquinolin-3-yl)carbamoyl]methyl]-N-ethylcarbamate

Into a 10-L 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of7-bromoquinoline-3,4-diamine (375 g, 1.58 mol, 1.00 equiv; Bioorg. Med.Chem. Lett, 2012, 22, 285) in ethyl acetate (6 L). To the solution wereadded pyridine (623 g, 7.88 mol, 5.00 equiv),2-[(tert-butoxy)carbonyl](ethyl)aminoacetic acid (480 g, 2.36 mol, 1.50equiv) and T₃P (2004 g, 3.15 mol, 2 equiv). The resulting solution wasstirred for 16 h at room temperature. The resulting mixture was washedwith sodium hydroxide aqueous (3×10 L) and brine (2×10 L). The resultingmixture was concentrated under vacuum. This resulted in 592 g (89%) oftert-butylN-[[(4-amino-7-bromoquinolin-3-yl)carbamoyl]methyl]-N-ethylcarbamate asa yellow solid.

Step 2. tert-ButylN-([7-bromo-1H-imidazo[4,5-c]quinolin-2-yl]methyl)-N-ethylcarbamate

Into a 10-L round-bottom flask, was placed a solution of tert-butylN-[[(4-amino-7-bromoquinolin-3-yl)carbamoyl]methyl]-N-ethylcarbamate(592 g, 1.40 mol, 1.00 equiv) in ethanol (6 L). To the solution, sodiumhydroxide (558 g, 13.95 mol, 10.00 equiv) was added. The resultingsolution was stirred for 1 h at 80° C. in an oil bath. The resultingmixture was concentrated under vacuum and diluted with 5 L of DCM. Theresulting mixture was washed with brine (5×10 L), dried over anhydroussodium sulfate and concentrated under vacuum. This resulted in 400 g(71%) of tert-butylN-([7-bromo-1H-imidazo[4,5-c]quinolin-2-yl]methyl)-N-ethylcarbamate as ayellow solid.

Step 3.7-Bromo-2-([[(tert-butoxy)carbonyl](ethyl)amino]methyl)-1H-imidazo[4,5-c]quinolin-5-ium-5-olate

Into a 10-L 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of tert-butylN-([7-bromo-1H-imidazo[4,5-c]quinolin-2-yl]methyl)-N-ethylcarbamate (400g, 986.95 mmol, 1.00 equiv) in dichloromethane (6 L). To the solution,mCPBA (342 g, 1.98 mol, 2.00 equiv) was added. The resulting solutionwas stirred for 16 h at room temperature. The resulting mixture waswashed with sodium carbonate aqueous (3×10 L), dried over anhydroussodium sulfate and concentrated under vacuum. The residue was washedwith 5 L of ethyl acetate. The solids were collected by filtration. Thisresulted in 218.6 g (pure) and 341 g (crude) of7-bromo-2-([[(tert-butoxy)carbonyl](ethyl)amino]methyl)-1H-imidazo[4,5-c]quinolin-5-ium-5-olateas a light yellow solid.

Step 4. tert-butylN-([4-amino-7-bromo-1H-imidazo[4,5-c]quinolin-2-yl]methyl)-N-ethylcarbamate

Into a 5-L 3-necked round-bottom flask, was placed a solution of7-bromo-2-([[(tert-butoxy)carbonyl](ethyl)amino]methyl)-1H-imidazo[4,5-c]quinolin-5-ium-5-olate(214 g, 518.31 mmol, 1.00 equiv) in dichloromethane (3 L) and NH₃—H₂O (1L). To the solution, 4-methylbenzene-1-sulfonyl chloride (194 g, 1.037mol, 2.00 equiv) was then added. The resulting solution was stirred for6 h at room temperature. The solids were collected by filtration, washedwith DCM (3×2 L) and dried. This resulted in 188 g (86%) of tert-butylN-([4-amino-7-bromo-1H-imidazo[4,5-c]quinolin-2-yl]methyl)-N-ethylcarbamateas a light yellow solid.

Step 5. tert-butylN-[[4-amino-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-c]quinolin-2-yl]methyl]-N-ethylcarbamate

Into a 5-L round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of tert-butylN-([4-amino-7-bromo-1H-imidazo[4,5-c]quinolin-2-yl]methyl)-N-ethylcarbamate(156 g, 371.16 mmol, 1.00 equiv) in 1,4-dioxane/H₂O (3/0.3 L). To thesolution were added Cs₂CO₃ (363 g, 1.11 mol, 3.00 equiv),3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (144 g, 742.12 mmol,2.00 equiv) and Pd(dppf)Cl₂ dichloromethane complex (30 g, 36.72 mmol,0.10 equiv). The resulting solution was stirred for 24 h at 100° C. inan oil bath. The resulting solution was cooled to room temperature anddiluted with 3 L of H₂O. The solids were collected by filtration andapplied onto a silica gel column with dichloromethane/methanol (20/1).This resulted in 76.3 g (50%) of tert-butylN-[[4-amino-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-c]quinolin-2-yl]methyl]-N-ethylcarbamateas a yellow solid.

Step 6. Compound 101

Into a 5-L round-bottom flask, was placed a solution of tert-butylN-[[4-amino-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-c]quinolin-2-yl]methyl]-N-ethylcarbamate(75.6 g, 185.54 mmol, 1.00 equiv) in 1,4-dioxane/HCl (2 L, 4M). Theresulting solution was stirred for 16 h at room temperature. Theresulting mixture was concentrated under vacuum. The residue was made aslurry in 2 L of DCM and the solid was collected by filtration. Thisprocedure was repeated three times. Then the collected solid was driedand this resulted in 75.7 g (crude) of2-[(ethylamino)methyl]-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-c]quinolin-4-aminehydrochloride as a yellow solid. LC/MS [M⁺+H] 308.3. LC/MS Methodconditions: Column: BEH C18 2.1×50 mm; Mobile Phase A: water with 0.05%TFA; Mobile Phase B: acetonitrile with 0.05% TFA; Temperature: 50° C.;Gradient: 2-98% B over 1.7 min; Flow: 0.8 mL/min; LC RT=0.46 min. ¹H NMR(400 MHz, METHANOL-d₄) δ 8.11 (d, J=8.3 Hz, 1H), 8.04 (s, 1H), 7.84-7.77(m, 1H), 7.72 (s, 1H), 6.79 (d, J=2.1 Hz, 1H), 4.13 (s, 2H), 2.80 (q,J=7.2 Hz, 2H), 1.22 (t, J=7.2 Hz, 3H).

Example 3b. Preparation of1-ethyl-2-[(ethylamino)methyl]-7-(1H-pyrazol-5-yl)-1H-imidazo[4,5-c]quinolin-4-amine(Compound 464)

Step 1. 7-bromo-N-ethyl-3-nitroquinolin-4-amine

Into a 500-mL round-bottom flask was placed a solution of7-bromo-4-chloro-3-nitroquinoline (20 g, 62.61 mmol, 1 equiv, 90%) indichloromethane (300 mL). Then ethanamine (4.23 g, 93.91 mmol, 1.5equiv) and triethylamine (19.01 g, 187.83 mmol, 3 equiv) were added. Theresulting solution was stirred for 1 hour at room temperature. Thereaction was then quenched by the addition of water. The resultingsolution was extracted with 3×100 ml of dichloromethane and the organiclayers were combined. The solution was dried over anhydrous sodiumsulfate and concentrated. This resulted in 20 g of7-bromo-N-ethyl-3-nitroquinolin-4-amine as a yellow crude solid.

Step 2. 7-bromo-N⁴-ethylquinoline-3,4-diamine

Into a 1000-mL round-bottom flask, was placed a solution of7-bromo-N-ethyl-3-nitroquinolin-4-amine (20 g, 67.54 mmol, 1 equiv) inCH₃CN (500 mL). To the solution was added Pt/C (3 g, 15.38 mmol, 0.23equiv). The resulting solution was degassed and back filled with H₂. Theresulting solution was stirred for 24 hour at room temperature. Thesolids were filtered. The filtrate was concentrated to provide 19.7 g of7-bromo-N⁴-ethylquinoline-3,4-diamine as yellow crude oil. LC-MS: (ES,m/z): [M+H]⁺=226.1

Step 3. tert-butyl(2-((7-bromo-4-(ethylamino)quinolin-3-yl)amino)-2-oxoethyl)(ethyl)carbamate

Into a 1000-mL round-bottom flask was placed a solution of7-bromo-N⁴-ethylquinoline-3,4-diamine (10 g, 35.70 mmol, 1 equiv, 95%)and 2-[[(tert-butoxy)carbonyl](ethyl)amino]acetic acid (10.88 g, 53.54mmol, 1.5 equiv) in dichloromethane (500 mL). This was followed by theaddition of HATU (16.29 g, 42.83 mmol, 1.2 equiv) and DIEA (15.34 g,107.09 mmol, 3 equiv). The resulting solution was stirred for 3 hour atroom temperature. The reaction was then quenched by the addition ofwater. The resulting solution was extracted with 3×100 ml ofdichloromethane and the organic layers were combined. The solution wasdried over anhydrous sodium sulfate and concentrated. This resulted in40 g (crude) of tert-butylN-([[7-bromo-4-(ethylamino)quinolin-3-yl]carbamoyl]methyl)-N-ethylcarbamateas yellow oil.

Step 4. tert-butylN-([7-bromo-1-ethyl-1H-imidazo[4,5-c]quinolin-2-yl]methyl)-N-ethylcarbamate

Into a 1000-mL round-bottom flask, was placed a solution of tert-butylN-[[(3-amino-7-bromoquinolin-4-yl)(ethyl)carbamoyl]methyl]-N-ethylcarbamate(40 g, 88.62 mmol, 1 equiv) in ethanol (500 mL) and water (20 mL). Tothe solution was added sodium hydroxide (35.45 g, 886.20 mmol, 10equiv). The resulting solution was stirred for 2 hours at 100° C. Theresulting mixture was concentrated. The residue was diluted with water.The resulting solution was then extracted with ethyl acetate and theorganic layers were combined. The solution was dried over anhydroussodium sulfate and concentrated. This resulted in 34.8 g (crude) oftert-butylN-([7-bromo-1-ethyl-1H-imidazo[4,5-c]quinolin-2-yl]methyl)-N-ethylcarbamateas yellow oil. LC-MS: (ES, m/z): [M+H]⁺=433.3

Step 5.7-bromo-2-([[(tert-butoxy)carbonyl](ethyl)amino]methyl)-1-ethyl-1H-imidazo[4,5-c]quinolin-5-ium-5-olate

Into a 1000-mL round-bottom flask, was placed tert-butylN-([7-bromo-1-ethyl-1H-imidazo[4,5-c]quinolin-2-yl]methyl)-N-ethylcarbamate(6 g, 13.85 mmol, 1 equiv) in dichloromethane (300 mL). This wasfollowed by the addition of m-CPBA (3.58 g, 20.77 mmol, 1.5 equiv) inportions. The resulting solution was stirred for 2 hour at roomtemperature. The reaction was then quenched by the addition of 150 mlH₂O. The resulting solution was extracted with DCM and the organiclayers were combined. The solution was dried over anhydrous sodiumsulfate and concentrated. This resulted in 7.5 g of7-bromo-2-([[(tert-butoxy)carbonyl](ethyl)amino]methyl)-1-ethyl-1H-imidazo[4,5-c]quinolin-5-ium-5-olateas a yellow crude solid.

Step 6. tert-butylN-([4-amino-7-bromo-1-ethyl-1H-imidazo[4,5-c]quinolin-2-yl]methyl)-N-ethylcarbamate

Into a 500-mL round-bottom flask, was placed7-bromo-2-([[(tert-butoxy)carbonyl](ethyl)amino]methyl)-1-ethyl-1H-imidazo[4,5-c]quinolin-5-ium-5-olate(6 g, 13.35 mmol, 1 equiv, crude) in dichloromethane (250 mL) and NH₃H₂O(5 mL, 20 mmol). This was followed by the addition of a solution of4-methylbenzene-1-sulfonyl chloride (5.09 g, 26.71 mmol, 2 equiv) indichloromethane (10 mL) dropwise with stirring. The resulting solutionwas stirred for 2 hour at room temperature. The reaction was thenquenched by the addition of water. The resulting solution was extractedwith dichloromethane and the organic layers were combined. The solutionwas dried over anhydrous sodium sulfate and concentrated. This resultedin 2 g of tert-butylN-([4-amino-7-bromo-1-ethyl-1H-imidazo[4,5-c]quinolin-2-yl]methyl)-N-ethylcarbamateas a white solid. LC-MS: (ES, m/z): [M+H]⁺=448.1. ¹H-NMR: (400 MHz,CD₃OD) δ 8.04-8.02 (m, 1H), 7.85-7.84 (m, 1H), 7.47-7.45 (m, 1H),4.84-4.82 (m, 2H), 4.67 (s, 2H), 3.35 (m, 2H), 1.5-1.29 (m, 12H),1.09-0.89 (m, 3H).

Step 7. tert-butylN-[[4-amino-1-ethyl-7-(1H-pyrazol-5-yl)-1H-imidazo[4,5-c]quinolin-2-yl]methyl]-N-ethylcarbamate

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of tert-butylN-([4-amino-7-bromo-1-ethyl-1H-imidazo[4,5-c]quinolin-2-yl]methyl)-N-ethylcarbamate(150 mg, 0.30 mmol, 1 equiv, 90%),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (116.8 mg,0.60 mmol, 2 equiv) in dioxane (25 mL) under N₂. To the solution wereadded Cs₂CO₃ (294.3 mg, 0.90 mmol, 3 equiv), and Pd(dppf)Cl₂ (11.0 mg,0.02 mmol, 0.05 equiv). The resulting solution was stirred for 24 hourat 100° C. The reaction was then quenched by the addition of water. Theresulting solution was extracted with ethyl acetate. The organic layerswere combined and dried over anhydrous sodium sulfate. The resultingmixture was concentrated. The residue was applied onto a silica gelcolumn and eluted with dichloromethane/methanol (10:1). This resulted in100 mg (76%) of tert-butylN-[[4-amino-1-ethyl-7-(1H-pyrazol-5-yl)-1H-imidazo[4,5-c]quinolin-2-yl]methyl]-N-ethylcarbamateas a yellow solid.

Step 8. Synthesis of Compound 465

Into a 250-mL round-bottom flask, was placed tert-butylN-[[4-amino-1-ethyl-7-(1H-pyrazol-5-yl)-1H-imidazo[4,5-c]quinolin-2-yl]methyl]-N-ethylcarbamate(100 mg, 0.23 mmol, 1 equiv) in dichloromethane (20 mL). This wasfollowed by the addition of HCl in dioxane (1.5 mL) dropwise withstirring. The resulting solution was stirred for 1 hour at roomtemperature. The resulting mixture was concentrated. The crude productwas purified by Prep-HPLC with the following conditions Column: SunFireC18 OBD Prep Column, 100 Å, 5 μm, 19 mm×250 mm; Mobile Phase A: Water(0.05% TFA), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 5% Bto 30% B in 8 min; 254/210 nm; Rt: 7.03 min. This resulted in 18 mg(13.77%) of1-ethyl-2-[(ethylamino)methyl]-7-(1H-pyrazol-5-yl)-1H-imidazo[4,5-c]quinolin-4-amine;bis(trifluoroacetic acid) as a white solid. LC Methods: Column: ExpressC18 2.1 mm×50 mm, 2.7 μm particles; Mobile Phase A: water with 0.05%TFA; Mobile Phase B: acetonitrile with 0.05% TFA; Temperature: 40° C.;Gradient: 5% B to 100% B over 2 min, then a 0.75 min hold at 100% B;Flow: 0.8 mL/min. LC retention time: 0.81 min. LC-MS: (ES, m/z):[M+H]⁺=336.3. ¹H-NMR: (300 MHz, CD₃OD, ppm) δ 8.38-8.35 (d, J=8.7 Hz,1H), 8.22 (m, 1H), 8.12-8.09 (m, 1H), 7.80-7.79 (d, J=2.8 Hz, 1H),6.89-6.86 (m, 1H), 4.76-4.69 (m, 4H), 3.45-3.38 (m, 2H), 1.63 (t, J=7.2Hz, 3H), 1.48 (t, J=7.2 Hz, 3H).

Example 3c. Preparation of1-ethyl-2-((ethylamino)methyl)-7-(1H-pyrazol-1-yl)-1H-imidazo[4,5-c]quinolin-4-amine(Compound 467)

Step 1. Synthesis of1-ethyl-2-[(ethylamino)methyl]-7-(1H-pyrazol-1-yl)-1H-imidazo[4,5-c]quinolin-4-amine

Into a 50-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed tert-butylN-([4-amino-7-bromo-1-ethyl-1H-imidazo[4,5-c]quinolin-2-yl]methyl)-N-ethylcarbamate(150 mg, 0.33 mmol, 1 equiv), 1H-pyrazole (45.6 mg, 0.67 mmol, 2 equiv)and K₃PO₄ (213.0 mg, 1.00 mmol, 3 equiv) in DMF (5 mL). Then(1S,2S)-cyclohexane-1,2-diamine (15.3 mg, 0.13 mmol, 0.4 equiv) and CuI(25.5 mg, 0.13 mmol, 0.4 equiv) were added. The resulting solution wasstirred for 24 hr at 100° C. under N₂ atmosphere. The reaction was thendiluted with water. The resulting solution was extracted with 3×50 ml ofethyl acetate and the organic layers were combined. The solution wasdried over anhydrous sodium sulfate and concentrated. The residue wasapplied onto a silica gel column with dichloromethane/methanol (10:1).This resulted in 100 mg (80.20%) of1-ethyl-2-[(ethylamino)methyl]-7-(1H-pyrazol-1-yl)-1H-imidazo[4,5-c]quinolin-4-amineas a white solid. LC-MS: (ES, m z): [M+H]⁺=436.2.

Step 2. Synthesis of Compound 468

Into a 50-mL round-bottom flask, was placed a solution of tert-butylN-[[4-amino-1-ethyl-7-(1H-pyrazol-1-yl)-1H-imidazo[4,5-c]quinolin-2-yl]methyl]-N-ethylcarbamate(100 mg, 0.23 mmol, 1 equiv) in DCM (10 mL). This was followed by theaddition of HCl in dioxane (1.5 mL) dropwise with stirring. Theresulting solution was stirred for 1 hr at room temperature. Theresulting mixture was concentrated. The crude product was purified byPrep-HPLC with the following conditions Column: SunFire C18 OBD PrepColumn, 100 Å, 5 μm, 19 mm×250 mm; Mobile Phase A: Water (0.05% TFA),Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 5% B to 30% B in 10min; 254/210 nm; Rt: 9.20 min. This resulted in 33.5 mg (25.64%) of1-ethyl-2-((ethylamino)methyl)-7-(1H-pyrazol-1-yl)-1H-imidazo[4,5-c]quinolin-4-amineas a white solid. LC-MS condition: Column: Kinetex EVO, 3.0 mm×50 mm,2.6 μm particles; Mobile Phase A: water with 5 mM ammonium bicarbonate;Mobile Phase B: acetonitrile; Temperature: 40° C.; Gradient: 10% B to95% B over 2 min, then a 0.79 min hold at 95% B; Flow: 1 m/min. LCretention time: 1.01 min. LC-MS: (ES, m/z): [M+H]⁺=336.3; 1H-NMR: 1H NMR(300 MHz, CD₃OD) δ 8.46-8.40 (m, 2H), 8.25-8.24 (m, 1H), 8.10-8.06 (m,1H), 7.84-7.83 (m, 1H), 6.64-6.63 (m, 1H), 4.72 (s, 2H), 4.70-4.63 (m,2H), 3.54-3.08 (m, 2H), 1.62 (t, J=6.0 Hz, 3H), 1.48 (t, J=9.0 Hz, 3H).

Example 3d. Preparation of2-[4-Amino-2-[(ethylamino)methyl]-7-(1H-pyrazol-5-yl)-1H-imidazo[4,5-c]quinolin-1-yl]ethan-1-ol(Compound 462)

Step 1. N-[2-(benzyloxy)ethyl]-7-bromo-3-nitroquinolin-4-amine

To a stirred mixture of 7-bromo-4-chloro-3-nitroquinoline (20 g, 69.57mmol, 1 equiv) and 2-(benzyloxy)ethan-1-amine (12.0 g, 79.30 mmol, 1.14equiv) in DCM (400 mL) was added TEA (10.6 g, 104.35 mmol, 1.50 equiv)at room temperature under nitrogen atmosphere. The resulting mixture wasstirred for 16 h at room temperature under nitrogen atmosphere. Theresulting mixture was concentrated under vacuum. This resulted inN-[2-(benzyloxy)ethyl]-7-bromo-3-nitroquinolin-4-amine (30 g) as ayellow crude solid. LC-MS: (ES, m/z): [M+H]⁺=402.2/404.2.

Step 2. N⁴-[2-(benzyloxy)ethyl]-7-bromoquinoline-3,4-diamine

To a solution of N-[2-(benzyloxy)ethyl]-7-bromo-3-nitroquinolin-4-amine(30 g, 74.58 mmol, 1 equiv) in CH₃CN (400 mL) was added Pt/C (2.9 g,14.87 mmol, 0.20 equiv) under nitrogen atmosphere in a 1000 mLround-bottom flask. The mixture was hydrogenated at room temperature for16 h under hydrogen atmosphere using a hydrogen balloon, filteredthrough a Celite pad and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography, eluted withCH₂Cl₂/MeOH (20:1) to affordN₄-[2-(benzyloxy)ethyl]-7-bromoquinoline-3,4-diamine (23.4 g, 84.28%) asa yellow solid. LC-MS: (ES, m/z): [M+H]⁺=372.3/374.2.

Step 3. tert-butylN-[[(4-[[2-(benzyloxy)ethyl]amino]-7-bromoquinolin-3-yl)carbamoyl]methyl]-N-ethylcarbamate

To a stirred mixture ofN4-[2-(benzyloxy)ethyl]-7-bromoquinoline-3,4-diamine (14.9 g, 40.03mmol, 1 equiv) and 2-[[(tert-butoxy)carbonyl](ethyl)amino]acetic acid(8.9 g, 44.03 mmol, 1.1 equiv) in DCM (500 mL) were added HATU (18.3 g,48.03 mmol, 1.2 equiv) and DIEA (10.3 g, 79.69 mmol, 1.99 equiv) at roomtemperature. The resulting mixture was stirred for 16 h at roomtemperature under nitrogen atmosphere. The resulting mixture wasconcentrated under vacuum. This resulted in tert-butylN-[[(4-[[2-(benzyloxy)ethyl]amino]-7-bromoquinolin-3-yl)carbamoyl]methyl]-N-ethylcarbamate(24 g, 107.56%) as a red crude oil. The crude product was used in thenext step directly without further purification. LC-MS: (ES, m/z):[M+H]⁺=557.2/559.2

Step 4. tert-butylN-([1-[2-(benzyloxy)ethyl]-7-bromo-1H-imidazo[4,5-c]quinolin-2-yl]methyl)-N-ethylcarbamate

A mixture of tert-butylN-[[(4-[[2-(benzyloxy)ethyl]amino]-7-bromoquinolin-3-yl)carbamoyl]methyl]-N-ethylcarbamate(23 g, 41.26 mmol, 1 equiv) and NaOH (3.3 g, 82.51 mmol, 2 equiv) inMeOH (250 mL) was stirred for 16 h at 65° C. The resulting mixture wasconcentrated under vacuum. The residue was purified by silica gel columnchromatography, eluted with PE/EtOAc (1.5:1) to afford tert-butylN-([1-[2-(benzyloxy)ethyl]-7-bromo-1H-imidazo[4,5-c]quinolin-2-yl]methyl)-N-ethylcarbamate(17.4 g, 78.18%) as alight yellow solid. LC-MS−: (ES, m/z):[M+H]³⁰=539.2/541.2 H-NMR: ¹H NMR (400 MHz, DMSO-d₆) δ 9.23 (s, 1H),8.42-8.31 (m, 2H), 7.75 (dd, J=8.9, 2.2 Hz, 1H), 7.14 (dd, J=5.0, 2.0Hz, 3H), 7.00 (dd, J=6.7, 2.9 Hz, 2H), 4.95 (s, 2H), 4.83 (s, 2H), 4.39(s, 2H), 3.86 (d, J=6.0 Hz, 2H), 2.51 (p, J=1.8 Hz, 2H), 1.38 (d, J=42.6Hz, 9H), 0.99 (t, J=7.0 Hz, 3H).

Step 5. tert-butylN-([1-[2-(benzyloxy)ethyl]-7-bromo-1H-imidazo[4,5-c]quinolin-2-yl]methyl)-N-ethylcarbamate

A mixture of1-[2-(benzyloxy)ethyl]-7-bromo-2-([[(tert-butoxy)carbonyl](ethyl)amino]methyl)-1H-imidazo[4,5-c]quinolin-5-ium-5-olate (2.1 g, 3.78 mmol,1 equiv) and mCPBA (1.0 g, 5.67 mol, 1.5 equiv) in DCM (35 mL) wasstirred for 4 h at room temperature under nitrogen atmosphere. Theresulting mixture was concentrated under vacuum. The residue waspurified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH(20:1) to afford tert-butylN-([1-[2-(benzyloxy)ethyl]-7-bromo-1H-imidazo[4,5-c]quinolin-2-yl]methyl)-N-ethylcarbamate(1.15 g, 56.39%) as an off-white solid. LC-MS: (ES, m/z):[M+H]⁺=555.2/557.2.

Step 6. tert-butylN-([4-amino-1-[2-(benzyloxy)ethyl]-7-bromo-1H-imidazo[4,5-c]quinolin-2-yl]methyl)-N-ethylcarbamate

To a stirred mixture of1-[2-(benzyloxy)ethyl]-7-bromo-2-([[(tert-butoxy)carbonyl](ethyl)amino]methyl)-1H-imidazo[4,5-c]quinolin-5-ium-5-olate(1.15 g, 2.07 mmol, 1 equiv) and NH₄OH (5 mL) in DCM (20 mL) were addedTsCl (0.8 g, 4.20 mol, 2.03 equiv) at room temperature. The resultingmixture was stirred for 1 h at room temperature. The resulting mixturewas concentrated under vacuum. The residue was purified by silica gelcolumn chromatography, eluted with CH₂Cl₂/MeOH (30:1) to affordtert-butylN-([4-amino-1-[2-(benzyloxy)ethyl]-7-bromo-1H-imidazo[4,5-c]quinolin-2-yl]methyl)-N-ethylcarbamate(775 mg, 67.51%) as an off-white solid. LC-MS: (ES, m/z):[M+H]⁺=554.2/556.2.

Step 7. tert-butylN-([4-amino-1-[2-(benzyloxy)ethyl]-7-(1H-pyrazol-5-yl)-1H-imidazo[4,5-c]quinolin-2-yl]methyl)-N-ethylcarbamate

To a solution of tert-butylN-([4-amino-1-[2-(benzyloxy)ethyl]-7-bromo-1H-imidazo[4,5-c]quinolin-2-yl]methyl)-N-ethylcarbamate(350 mg, 0.63 mmol, 1 equiv) and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (245.0 mg,1.26 mmol, 2.00 equiv) in dioxane (8 mL) and H₂O (0.8 mL) were addedK₂CO₃ (261.7 mg, 1.89 mmol, 3 equiv) and Pd(dppf)Cl₂CH₂Cl₂ (103.1 mg,0.13 mmol, 0.2 equiv) under a nitrogen atmosphere. After stirring for 20h at 90 degrees C. under a nitrogen atmosphere, the resulting mixturewas concentrated under reduced pressure. The residue was purified bysilica gel column chromatography, eluted with CH₂Cl₂/MeOH (20:1) toafford tert-butylN-([4-amino-1-[2-(benzyloxy)ethyl]-7-(1H-pyrazol-5-yl)-1H-imidazo[4,5-c]quinolin-2-yl]methyl)-N-ethylcarbamate(250 mg, 73.12%) as a brown solid. LC-MS: (ES, m/z): [M+H]⁺=542.2.

Step 8. Compound 463

A mixture of tert-butylN-([4-amino-1-[2-(benzyloxy)ethyl]-7-(1H-pyrazol-5-yl)-1H-imidazo[4,5-c]quinolin-2-yl]methyl)-N-ethylcarbamate(210 mg, 390 mmol, 1 equiv) in HCl in dioxane (10 mL, 4 mol/L) wasstirred for 24 h at 60° C. The resulting mixture was concentrated undervacuum. The crude product was purified by Prep-HPLC with the followingconditions (Column: XBridge Prep C18 OBD Column, 5 um, 19*150 mm; MobilePhase A: Water (10 MMOL/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 25mL/min; Gradient: 12% B to 26% B in 10 min; 254/210 nm; Rt: 8.63 min) toafford2-[4-amino-2-[(ethylamino)methyl]-7-(1H-pyrazol-5-yl)-1H-imidazo[4,5-c]quinolin-1-yl]ethan-1-ol(8.1 mg, 5.95%) as a white solid. LC Methods: Column: Shim-pack XR-ODS3.0 mm×50 mm, 2.2 μm particles; Mobile Phase A: water with 0.05% TFA;Mobile Phase B: acetonitrile with 0.05% TFA; Temperature: 40° C.;Gradient: 0% B to 95% B over 2 min, then a 0.7 min hold at 95% B; Flow:1.5 mL/min. LC retention time: 0.76 min. LC-MS: (ES, m/z): [M+H]⁺=352.3H-NMR: ¹H NMR (300 MHz, DMSO-d₆) δ 13.15 (m, 1H), 8.16-7.95 (m, 2H),7.89-7.48 (m, 2H), 6.80 (s, 1H), 6.54 (s, 2H), 5.57 (s, 1H), 4.75 (d,J=6.3 Hz, 2H), 4.05 (s, 2H), 3.91 (t, J=5.3 Hz, 2H), 2.61 (q, J=7.1 Hz,2H), 1.04 (t, J=7.0 Hz, 3H).

The compounds in Table 3 were prepared procedures found above.

TABLE 3 LC/MS LC Cmpd Name [M⁺ + H] LC RT Method 4681-ethyl-2-[(ethylamino)methyl]-7- 352.1 1.29 min A(thiophen-2-yl)-1H-imidazo[4,5-c] quinolin-4-amine 4712-{4-amino-2-[(ethylamino)methyl]-7- 368.1 1.12 min B(thiophen-2-yl)-1H-imidazo[4,5-c] quinolin-1-yl}ethan-1-ol 4772-[4-amino-2-[(ethylamino)methyl]-7- 352.0 0.92 min B(1H-pyrazol-1-yl)-1H-imidazo[4,5-c] quinolin-l-yl]ethan-1-ol LC Methods:A: Column: Kinetex EVO, 3.0 mm × 50 mm, 2.6 μm particles; Mobile PhaseA: water with 5 mM ammonium bicarbonate; Mobile Phase B: acetonitrile;Temperature: 40° C.; Gradient: 10% B to 95% B over 2 min, then a 0.79min hold at 95% B; Flow: 1 mL/min. B: Column: Kinetex EVO, 3.0 mm × 50mm, 2.6 μm particles; Mobile Phase A: water with 0.03% NH3H2O; MobilePhase B: acetonitrile; Temperature: 40° C.; Gradient: 10% B to 95% Bover 2 min, then a 0.60 min hold at 95% B; Flow: 1.2 mL/min

Example 4: Example Preparation Method of Analogs Wherein R¹/R²=H, Alkyl,Acetyl, Sulfonyl, Carbonyl, Amido, Carboxy and R⁵=Aryl, Heteroaryl,Heterocyclyl. or Amino Example 4a. Example Procedure for Acetamideformation

Preparation ofN-[[4-amino-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-c]quinolin-2-yl]methyl]-N-ethylacetamide(Compound 112)

Into a 5-L round-bottom flask, was placed a solution of2-[(ethylamino)methyl]-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine(75.7 g, 245.97 mmol, 1.00 equiv, Example 3a) in dichloromethane (2 L).To the solution, TEA (124 g, 1.23 mol, 5.00 equiv) and acetic anhydride(50 g, 490.20 mmol, 2.00 equiv) were added. The resulting solution wasstirred for 6 h at room temperature. Then the resulting mixture wasconcentrated under vacuum. The residue was dissolved in 3 L of MeOH andallowed to react with stirring for an additional 16 h while thetemperature was maintained at 80° C. in an oil bath. The reactionmixture was cooled to room temperature, and evaporated to get the crudeproduct. The crude material was stirred with 2 L of DCM and the solidwas collected by filtration. This procedure was repeated three times.The resulting solid was stirred with 3 L of water and the pH wasadjusted to 10 by the addition of aqueous NH₃. The precipitated solidwas collected by filtration. The mother liquor was evaporated and theresulting precipitate was collected by filtration (3×). The combinedsolid was dissolved in methanol and stirred with 10% Si-thiol at refluxfor 4-6 hours and filtered. The filtrate was evaporated to get the crudeproduct. This procedure was repeated until the Pd content in theresulting product was <50 ppm. The crude product was washed with 3×250mL of water, collected by filtration and dried. This resulted in 20.28 g(24%) of Compound 112 as a light yellow solid.

¹H NMR (400 MHz, MeOD, ppm) δ: 8.15-8.07 (m, 1H), 7.98 (s, 1H),7.80-7.67 (m, 2H), 6.80-6.70 (m, 1H), 4.88-4.85 (m, 2H), 3.60-3.48 (m,2H), 2.30-2.20 (m, 3H), 1.23 (t, J=7.2 Hz, 2H), 1.11 (t, J=7.2 Hz, 1H);LC/MS [M⁺+H] 350.1. LC/MS Method conditions: Column: Shim-pack XR-ODS3.0×50 mm, 2.2 μm particles; Mobile Phase A: water with 0.05% TFA;Mobile Phase B: acetonitrile with 0.05% TFA; Temperature: 40° C.;Gradient: 5-100% B over 3.8 min; Flow: 1.2 mL/min; 5 min run time. LC RT1.349 min.

Preparation ofN-[[4-amino-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-c]quinolin-2-yl]methyl]-N-ethylacetamide(Compound 112, Alternate Procedure)

2-[(Ethylamino)methyl]-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-c]quinolin-4-aminehydrochloride (107 g, 311 mmol) and CH₂Cl₂ (1.6 L) was stirred at roomtemperature. Et₃N (130 mL, 3 equiv) was added over 15 to 30 minutes,maintaining the temperature between 15-25° C. Acetic anhydride (41 mL,1.4 eq) was added over 15 to 30 min, and the reaction mixture wasstirred for 90 min. CH₃OH (54 mL) was added, and the reaction wasstirred for 20 minutes before concentrating under reduced pressure. Thecrude material was treated with MeOH (2.2 L) and stirred at 60-70° C.for 2 h. After cooling to rt, the crude product was collected byfiltration and washed with CH₃OH (220 mL). The resulting solid was driedunder vacuum and then stirred into n-butanol (5.4 L) and H₂O (1.3 L).The mixture was heated to 60° C. and the pH was adjusted to 8 with 20%aqueous Na₂CO₃ solution (˜60 mL). The organic layer was separated andthe aqueous layer was extracted with an additional portion of n-butanol(540 mL) at 60° C. The combined organic layers were washed with brine(540 mL) at 50° C. for 15 minutes (2×) and concentrated under reducedpressure. The crude product was treated with CH₃OH (7.6 L) and H₂O (540mL) and heated to 70° C. SiliaMetS-Thiol (22 g) was added and themixture was stirred for 2 h, then filtered at 60° C. The filter cake waswashed with CH₃OH (220 mL). The filtrate was concentrated under reducedpressure to ca. 800 mL, and stirred at rt for 2 h. The precipitate wasfiltered and washed with MeOH (220 mL), and H₂O (2×220 mL). Theresulting solid was dried under vacuum and N₂, then transferred to a100° C. vacuum oven to complete the drying process. This afforded 83.5 g(77%) of Compound 112.

Example 4b. Example Procedure for Amide Formation

Preparation ofN-{[4-amino-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-c]quinolin-2-yl]methyl}-N-ethyl-3-hydroxy-3-methylbutanamide(Compound 440)

To a suspension of 3-hydroxy-3-methylbutanoic acid (10.31 mg, 0.087mmol) and2-((ethylamino)methyl)-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine,HCl (20 mg, 0.058 mmol) in DMF (582 μl) was added Hunig's Base (25.4 μl,0.145 mmol) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane2,4,6-trioxide (50% in DMF) (37.2 μl, 0.064 mmol). The reaction wasstirred at rt overnight, then diluted with MeOH and purified bypreparative HPLC with the following conditions: Column: XBridge C18, 200mm×19 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with0.10% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with0.1% trifluoroacetic acid; Gradient: a 0-minute hold at 13% B, 13-38% Bover 25 minutes, then a 2-minute hold at 100% B; Flow Rate: 20 mL/min;Column Temperature: 25° C. Fractions containing the desired product werecombined and dried via centrifugal evaporation to giveN-{[4-amino-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-c]quinolin-2-yl]methyl}-N-ethyl-3-hydroxy-3-methylbutanamideas the bis trifluoroacetate salt (8.4 mg, 22%). ¹H NMR (500 MHz,DMSO-d₆) δ 8.78 (br d, J=14.6 Hz, 1H), 8.38-8.12 (m, 2H), 8.00 (br s,1H), 7.81 (s, 1H), 6.82 (br s, 1H), 5.03-4.73 (m, 2H), 3.65-3.41 (m,2H), 2.64-2.54 (m, 2H), 1.31-0.84 (m, 9H). LC/MS Conditions: Column:Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50°C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100%B; Flow: 1.0 mL/min. LC RT: 0.933 min. M/Z=408.3.

Example 4c. Example Procedure for Carbamate Formation

Preparation of EthylN-{[4-amino-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-c]quinolin-2-yl]methyl}-N-ethylcarbamate(Compound 436)

2-((Ethylamino)methyl)-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine(15 mg, 0.049 mmol) was suspended in CH₂Cl₂ (488 μl) at rt. Pyridine(15.79 μl, 0.195 mmol) was added, followed by ethyl chloroformate (9.37μl, 0.098 mmol). After 2 days, the reaction was concentrated andredissolved in MeOH. TEA (13.60 μl, 0.098 mmol) was added, and thereaction was stirred at rt overnight. The reaction was diluted with MeOHand purified via preparative LC/MS with the following conditions:Column: XBridge C18, 200 mm×19 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: a 0-minutehold at 4% B, 4-44% B over 20 minutes, then a 4-minute hold at 100% B;Flow Rate: 20 mL/min; Column Temperature: 25° C. Fractions containingthe desired product were combined and dried via centrifugal evaporationto give ethylN-{[4-amino-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-c]quinolin-2-yl]methyl}-N-ethylcarbamate(7.4 mg, 39%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.12 (br d, J=8.2 Hz, 1H),7.98 (s, 1H), 7.70 (br d, J=8.5 Hz, 2H), 6.77 (s, 1H), 4.72 (s, 2H),4.11 (br s, 2H), 3.52-3.32 (m, 2H), 1.29-1.11 (m, 3H), 1.08 (br t, J=6.9Hz, 3H). LC/MS conditions: Column: Waters XBridge C18, 2.1 mm×50 mm, 1.7μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mMammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mMammonium acetate; Temperature: 50° C.; Gradient: 0% B to 100% B over 3min, then a 0.75 min hold at 100% B; Flow: 1 m/min. LC RT: 1.29 min.M/Z=390.0.

Example 4d. Example Procedure for Sulfonamide Formation

Preparation ofN-{[4-amino-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-c]quinolin-2-yl]methyl}-N-ethylpropane-2-sulfonamide(Compound 459)

To a solution of propane-2-sulfonyl chloride (10.37 mg, 0.073 mmol) inDMF (582 μl) was added2-((ethylamino)methyl)-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine,HCl (20 mg, 0.058 mmol) and Hunig's Base (25.4 μl, 0.145 mmol). Thereaction was stirred at rt overnight, then diluted with DMF and purifiedvia preparative LC/MS with the following conditions: Column: XBridgeC18, 200 mm×19 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5acetonitrile:water with 0.10% trifluoroacetic acid; Gradient: a 0-minutehold at 3% B, 3-43% B over 30 minutes, then a 4-minute hold at 100% B;Flow Rate: 20 mL/min; Column Temperature: 25° C. Fractions containingthe desired product were combined and dried via centrifugal evaporationto giveN-{[4-amino-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-c]quinolin-2-yl]methyl}-N-ethylpropane-2-sulfonamide(1.4 mg, 4.6%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.28 (br s, 1H), 8.20 (br s,1H), 8.02-7.95 (m, 1H), 7.89-7.82 (m, 1H), 6.83 (br s, 1H), 4.73 (br s,2H), 3.53-3.40 (m, 2H), 3.31 (br s, 1H), 1.24 (br d, J=6.4 Hz, 6H), 1.13(br t, J=6.9 Hz, 3H). LC/MS conditions: Column: Waters XBridge C18, 2.1mm×50 mm, 1.7 μm particles; Mobile Phase A: 5:95 acetonitrile:water with10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10mM ammonium acetate; Temperature: 50° C.; Gradient: 0% B to 100% B over3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min. LC RT: 1.24 min.M/Z=413.9.

Example 4e. Example Procedure for Urea Formation with CarbamoylChlorides

Preparation ofN-{[4-amino-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-c]quinolin-2-yl]methyl}-N-ethylmorpholine-4-carboxamide(Compound 455)

To a suspension of2-((ethylamino)methyl)-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine,HCl (20 mg, 0.058 mmol) in DMF (582 μl) was added Hunig's Base (25.4 μl,0.145 mmol) and morpholine-4-carbonyl chloride (10.18 μl, 0.087 mmol).After ca. 1.5 hours, the reaction was quenched with MeOH, filteredthrough a syringe filter, and purified by preparative HPLC with thefollowing conditions: Column: XBridge C18, 200 mm×19 mm, 5-μm particles;Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate;Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate;Gradient: a 0-minute hold at 0% B, 0-40% B over 20 minutes, then a4-minute hold at 100% B; Flow Rate: 20 mL/min; Column Temperature: 25°C. Fractions containing the desired product were combined and dried viacentrifugal evaporation to giveN-{[4-amino-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-c]quinolin-2-yl]methyl}-N-ethylmorpholine-4-carboxamide(14.9 mg, 60%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.09 (br d, J=7.9 Hz, 1H),8.01-7.90 (m, 1H), 7.74-7.63 (m, 2H), 6.76 (s, 1H), 4.59 (s, 2H), 3.60(br s, 2H), 3.27-3.18 (m, 4H), 1.90 (s, 4H), 1.10 (br t, J=6.7 Hz, 3H).LC/MS Conditions: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammoniumacetate; Temperature: 50° C.; Gradient: 0-100% B over 3 minutes, then a0.75-minute hold at 100% B; Flow: 1.0 mL/min. LC RT: 0.914 min,M/Z=421.4.

Example 4f. Example Procedure for Urea Formation with Isocyanates

Preparation of1-{[4-amino-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-c]quinolin-2-yl]methyl}-1,3-diethylurea(Compound 457)

To a suspension of2-((ethylamino)methyl)-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine,HCl (20 mg, 0.058 mmol) in DMF (582 μl) was added Hunig's Base (25.4 μl,0.145 mmol) and isocyanatoethane (5.76 μl, 0.073 mmol). After 1.5 hours,the reaction was quenched with MeOH, filtered through a syringe filter,and purified by preparative HPLC with the following conditions: Column:XBridge C18, 200 mm×19 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: a 0-minutehold at 0% B, 0-40% B over 20 minutes, then a 4-minute hold at 100% B;Flow Rate: 20 mL/min; Column Temperature: 25° C. Fractions containingthe desired product were combined and dried via centrifugal evaporationto give1-{[4-amino-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-c]quinolin-2-yl]methyl}-1,3-diethylurea(4.8 mg, 21%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.13 (br d, J=8.2 Hz, 1H),7.97 (s, 1H), 7.73-7.63 (m, 2H), 6.81-6.73 (m, 1H), 6.58 (br s, 1H),4.68 (s, 2H), 3.36-3.26 (m, 2H), 3.17-3.07 (m, 2H), 1.09-0.96 (m, 6H).LC/MS Conditions: Column: Waters XBridge C18, 2.1 mm×50 mm, 1.7 μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammoniumacetate; Temperature: 50° C.; Gradient: 0% B to 100% B over 3 min, thena 0.75 min hold at 100% B; Flow: 1 mL/min. LC RT: 0.82 min. M/Z=379.3.

Example 4g. Example Procedure for Sulfonylurea Formation

Preparation of2-{1[(dimethylsulfamoyl)(ethyl)amino]methyl}-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine(Compound 458)

To a suspension of2-((ethylamino)methyl)-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine,HCl (20 mg, 0.058 mmol) in DMF (582 μl) was added Hunig's Base (25.4 μl,0.145 mmol) and dimethylsulfamoyl chloride (10.44 mg, 0.073 mmol). Thereaction was stirred at rt overnight, then quenched with MeOH, filteredthrough a syringe filter, and purified via preparative LC/MS with thefollowing conditions: Column: XBridge C18, 200 mm×19 mm, 5-μm particles;Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid;Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid;Gradient: a 0-minute hold at 16% B, 16-40% B over 25 minutes, then a2-minute hold at 100% B; Flow Rate: 20 mL/min; Column Temperature: 25°C. Fractions containing the desired product were combined and dried viacentrifugal evaporation to give2-{[(dimethylsulfamoyl)(ethyl)amino]methyl}-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-c]quinolin-4-amineas the bis-trifluoroacetate salt (13.5 mg, 35%). ¹H NMR (500 MHz,DMSO-d₆) δ 8.32 (br d, J=8.3 Hz, 1H), 8.22 (br s, 1H), 8.00 (br d, J=7.8Hz, 1H), 7.82 (br s, 1H), 6.82 (d, J=1.9 Hz, 1H), 4.68 (s, 2H), 3.43 (q,J=7.0 Hz, 2H), 2.75 (s, 6H), 1.17 (t, J=7.1 Hz, 3H). LC/MS conditions:Column: Waters XBridge C18, 2.1 mm×50 mm, 1.7 μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50°C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B;Flow: 1 mL/min. LC RT: 1.17 min. M/Z=415.04.

Example 4h. Example Procedure for Amine Formation

Preparation of2-{[ethyl(2-methylpropyl)amino]methyl}-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine(Compound 453)

To a suspension of isobutyraldehyde (20.97 mg, 0.291 mmol) and2-((ethylamino)methyl)-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine,HCl (20 mg, 0.058 mmol) in MeOH (582 μl) was added sodiumtriacetoxyborohydride (37.0 mg, 0.175 mmol). After 4.5 hours,isobutyraldehyde (20.97 mg, 0.291 mmol) and sodium triacetoxyborohydride(37.0 mg, 0.175 mmol) were added. After 2.75 hours, the reaction waspartially concentrated, diluted with water and extracted three timeswith EtOAC. The organic layers were concentrated. The residue wasdissolved in DMF, filtered through a syringe filter, and purified bypreparative HPLC with the following conditions: Column: XBridge C18, 200mm×19 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with10-mM ammonium acetate; Gradient: a 0-minute hold at 20% B, 20-44% Bover 25 minutes, then a 2-minute hold at 100% B; Flow Rate: 20 mL/min;Column Temperature: 25° C. Fractions containing the desired product werecombined and dried via centrifugal evaporation to give2-{[ethyl(2-methylpropyl)amino]methyl}-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine(1.1 mg, 5.2%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.15 (d, J=8.2 Hz, 1H), 7.98(s, 1H), 7.72-7.64 (m, 2H), 6.73 (d, J=1.9 Hz, 1H), 3.86 (s, 2H), 2.61(q, J=7.0 Hz, 2H), 2.27 (d, J=7.1 Hz, 2H), 1.78-1.69 (m, 1H), 1.06 (t,J=7.0 Hz, 3H), 0.86 (d, J=6.6 Hz, 6H). LC/MS Conditions: Column: WatersXBridge C18, 2.1 mm×50 mm, 1.7 μm particles; Mobile Phase A: 5:95acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10 mM ammonium acetate; Temperature: 50° C.;Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B;Flow: 1 mL/min; LC RT: 1.36 min; M/Z=364.1.

The compounds of Table 4 were prepared using the procedures outlinedabove. LC/MS Method conditions: Column: BEH C18 2.1×50 mm; Mobile PhaseA: water with 0.05% TFA; Mobile Phase B: acetonitrile with 0.05% TFA;Temperature: 50° C.; Gradient: 2-98% B over 1.7 min; Flow: 0.8 mL/min.

TABLE 4 LC/MS Cmpd Name [M⁺ + H] LC RT NMR Data 102 N-((4-Amino-7-(1H-336.3 0.54 min ¹HNMR (400 MHz, METHANOL-d₄) pyrazol-1-yl)-1H- δ8.36-8.31 (m, 1H), 8.26-8.16 imidazo[4,5-c]quinolin-2-yl) (m, 1H),8.02-7.96 (m, 1H), 7.81-7.75 methyl)-N-methylacetamide (m, 2H),6.61-6.58 (m, 1H), 4.95-4.92 (m, 2H), 3.23 (s, 2H), 3.07 (s, 1H), 2.32(s, 1H), 2.26 (s, 2H) 106 2-((Ethylamino)methyl)- 322.1 0.48 min ¹HNMR(400 MHz, METHANOL-d₄) 1-methyl-7-(1H-pyrazol- δ 8.30 (br d, J = 8.6 Hz,1H) 3-yl)-1H-imidazo[4,5-c] 8.15-7.98 (m, 1H), 7.89-7.64 (m, 2H),quinolin-4-amine 6.79 (s, 1H), 4.24 (s, 3H), 4.12 (s, 2H), 2.80 (q, J =7.2 Hz, 2H), 1.21 (t, J = 7.2 Hz, 3H) 108 N-((4-Amino-7-(1H- 386.3 0.59min ¹HNMR (400 MHz, METHANOL-d₄) pyrazol-1-yl)-1H- δ 8.34 (d, J = 2.4Hz, 1H), imidazo[4,5-c]quinolin-2-yl) 8.30-8.20 (m, 1H), 7.99 (d, J =2.1 Hz, methyl)-N-ethylmethanesulfonamide 1H), 7.82-7.75 (m, 2H), 6.59(t, J = 2.1 Hz, 1H), 4.77 (s, 2H), 3.46 (q, J = 7.1 Hz, 2H), 3.04 *s,3H), 1.22 (t, J = 7.1 Hz, 3H) 109 tert-Butyl ((4-amino-7- 408.3 0.69 min¹HNMR (400 MHz, METHANOL-d₄) (1H-pyrazol-3-yl)-1H- δ 8.22-8.09 (m, 1H),8.07-7.98 imidazo[4,5-c]quinolin-2-yl) (m, 1H), 7.91-7.51 (m, 2H), 6.79methyl)(ethyl)carbamate (br s, 1H), 4.77 (s, 2H), 3.63-3.42 (m, 2H),1.64-1.32 (m, 9H), 1.19 (br s, 3H) 110 1-((4-Amino-7-(1H- 379.3 0.58 min¹HNMR (400 MHz, METHANOL-d₄) pyrazol-3-yl)-1H- δ 8.25-8.10 (m, 1H),8.09-7.99 imidazo[4,5-c]quinolin-2-yl) (m, 1H), 7.91-7.65 (m, 2H), 6.79methyl)-1-ethyl-3,3- (br s, 1H), 4.67 (s, 2H), 3.39-3.34 dimethylurea(m, 2H), 2.97 (s, 6H), 1.23 (t, J = 7.1 Hz, 3H) 113 N-((4-Amino-7-(1H-322.3 0.49 min ¹HNMR (400 MHz, METHANOL-d₄) pyrazol-3-yl)-1H- δ 8.13 (brd, J = 8.3 Hz, 1H), 8.03 imidazo[4,5-c]quinolin-2-yl) (br s, 1H),7.88-7.65 (m, 2H), 6.78 methyl)acetamide (s, 1H), 4.71 (s, 2H), 2.11 (s,3H) 158 N-((4-Amino-7-methoxy- 314.3 0.55 min ¹HNMR (400 MHz,METHANOL-d₄) 1H-imidazo[4,5-c] δ 8.07-7.95 (m, 1H), 7.13 (d,quinolin-2-yl)methyl)- J = 2.2 Hz, 1H), 7.07-6.97 (m, 1H),N-ethylacetamide 3.92 (s, 1H), 3.91 (s, 2H), 3.61-3.50 (m, 2H), 2.29 (s,1H), 2.26 (s, 2H), 1.26 (t, J = 7.1 Hz, 2H), 1.13 (t, J = 7.1 Hz, 1H)419 N-((4-Amino-7- 366.3 0.65 min ¹HNMR (400 MHz, METHANOL-d₄)(thiophen-3-yl)-1H-imidazo δ 8.20-8.10 (m, 1H), 7.94-7.90[4,5-c]quinolin-2-yl) (m, 1H), 7.80-7.75 (m, 1H), 7.75-7.67methyl)-N-ethylacetamide (m, 1H), 7.62-7.53 (m, 2H), 4.91 (s, 2H),3.66-3.52 (m, 2H), 2.31 (s, 1H), 2.27 (s, 2H), 1.27 (t, J = 7.2 Hz, 2H),1.15 (t, J = 7.1 Hz, 1H)

The compounds of Table 5 were prepared using the procedures outlinedabove.

TABLE 5 LC/MS LC Cmpd Name [M⁺ + H] LC RT Method 436 ethylN-{[4-amino-7-(1H-pyrazol-3-yl)-1H- 390.0 1.29 min Aimidazo[4,5-c]quinolin-2-yl]methyl}-N- ethylcarbamate 437N-{[4-amino-7-(1H-pyrazol-3-yl)-1H- 440.4 1.30 min Aimidazo[4,5-c]quinolin-2-yl]methyl}-N- ethyl-2-(3-methylphenyl)acetamide438 N-{[4-amino-7-(1H-pyrazol-3-yl)-1H- 413.0 1.13 min Bimidazo[4,5-c]quinolin-2-yl]methyl}-N- ethylpyridine-3-carboxamide 439N-{[4-amino-7-(1H-pyrazol-3-yl)-1H- 413.2 1.19 min Bimidazo[4,5-c]quinolin-2-yl]methyl}-N- ethylpyridine-2-carboxamide 440N-{[4-amino-7-(1H-pyrazol-3-yl)-1H- 408.4 0.97 min Bimidazo[4,5-c]quinolin-2-yl]methyl}-N-ethyl-3-hydroxy-3-methylbutanamide 441N-{[4-amino-7-(1H-pyrazol-3-yl)-1H- 442.01 1.21 min Aimidazo[4,5-c]quinolin-2-yl]methyl}-N- ethyl-4-methoxybenzamide 442N-{[4-amino-7-(1H-pyrazol-3-yl)-1H- 414.0 0.88 min Aimidazo[4,5-c]quinolin-2-yl]methyl}-N- ethylpyrazine-2-carboxamide 443N-{[4-amino-7-(1H-pyrazol-3-yl)-1H- 426.0 1.26 min Bimidazo[4,5-c]quinolin-2-yl]methyl}-N- ethyl-2-phenylacetamide 444N-{[4-amino-7-(1H-pyrazol-3-yl)-1H- 454.1 1.48 min Aimidazo[4,5-c]quinolin-2-yl]methyl}-N- ethyl-4-phenylbutanamide 445N-{[4-amino-7-(1H-pyrazol-3-yl)-1H- 406.1 1.41 min Aimidazo[4,5-c]quinolin-2-yl]methyl}-N- ethyl-4-methylpentanamide 446N-{[4-amino-7-(1H-pyrazol-3-yl)-1H- 415.2 1.17 min Aimidazo[4,5-c]quinolin-2-yl]methyl}-N-ethyl-1-methyl-1H-pyrrole-2-carboxamide 447N-{[4-amino-7-(1H-pyrazol-3-yl)-1H- 440.2 1.37 min Aimidazo[4,5-c]quinolin-2-yl]methyl}-N- ethyl-3-phenylpropanamide 448N-{[4-amino-7-(1H-pyrazol-3-yl)-1H- 419.3 1.12 min Aimidazo[4,5-c]quinolin-2-yl]methyl}-N- ethyl-1,3-thiazole-4-carboxamide449 N-{[4-amino-7-(1H-pyrazol-3-yl)-1H- 446.0 1.28 min Aimidazo[4,5-c]quinolin-2-yl]methyl}-2- chloro-N-ethylbenzamide 450N-{[4-amino-7-(1H-pyrazol-3-yl)-1H- 413.0 0.92 min Aimidazo[4,5-c]quinolin-2-yl]methyl}-N- ethylpyridine-4-carboxamide 451N-{[4-amino-7-(1H-pyrazol-3-yl)-1H- 465.2 1.31 min Bimidazo[4,5-c]quinolin-2-yl]methyl}-N-ethyl-1-methyl-1H-indole-3-carboxamide 452N-{[4-amino-7-(1H-pyrazol-3-yl)-1H- 446.0 1.36 min Aimidazo[4,5-c]quinolin-2-yl]methyl}-4- chloro-N-ethylbenzamide 4532-{[ethyl(2-methylpropyl)amino]methyl}-7- 364.1 1.36 min A(1H-pyrazol-3-yl)-1H-imidazo[4,5-c] quinolin-4-amine 4541-{[4-amino-7-(1H-pyrazol-3-yl)-1H-imidazo 407.1 1.3 min A[4,5-c]quinolin-2-yl]methyl}-1,3,3-triethylurea 455N-{[4-amino-7-(1H-pyrazol-3-yl)-1H- 421.4 0.91 min Bimidazo[4,5-c]quinolin-2-yl]methyl}-N- ethylmorpholine-4-carboxamide 4561-{[4-amino-7-(1H-pyrazol-3-yl)-1H-imidazo 407.1 1.29 min A[4,5-c]quinolin-2-yl]methyl}-3-tert-butyl-1-ethylurea 4571-{[4-amino-7-(1H-pyrazol-3-yl)-1H-imidazo 379.3 0.82 min A[4,5-c]quinolin-2-yl]methyl}-1,3-diethylurea 4582-{[(dimethylsulfamoyl)(ethyl)amino] 415.0 1.17 min Amethyl}-7-(1H-pyrazol-3-yl)-1H-imidazo [4,5-c]quinolin-4-amine 459N-{[4-amino-7-(1H-pyrazol-3-yl)-1H- 413.9 1.24 min Aimidazo[4,5-c]quinolin-2-yl]methyl]-N- ethylpropane-2-sulfonamide 460N-{[4-amino-7-(1H-pyrazol-3-yl)-1H- 414.0 1.16 min Aimidazo[4,5-c]quinolin-2-yl]methyl}-N- ethylpropane-1-sulfonamide 470N-{[4-amino-1-(2-hydroxyethyl)-7- 424.1 1.24 min D(thiophen-2-yl)-1H-imidazo[4,5-c]quinolin-2-yl]methyl}-N-ethylpropanamide 472N-{[4-amino-1-ethyl-7-(thiophen-2-yl)-1H-imidazo 393.9 2.27 min E[4,5-c]quinolin-2-yl]methyl}-N-ethylacetamide 473N-{[4-amino-1-ethyl-7-(1H-pyrazol-5-yl)-1H-imidazo 392.3 1.75 min E[4,5-c]quinolin-2-yl]methyl}-N-ethylpropanamide 474N-{[4-amino-1-ethyl-7-(1H-pyrazol-5-yl)-1H-imidazo 378.3 1.95 min C[4,5-c]quinolin-2-yl]methyl}-N-ethylacetamide 475N-{[4-amino-1-(2-hydroxyethyl)-7-(1H-pyrazol-5-yl)- 408.1 0.92 min D1H-imidazo[4,5-c]quinolin-2-yl]methyl}- N-ethylpropanamide 476N-{[4-amino-1-(2-hydroxyethyl)-7-(1H-pyrazol-1-yl)- 394.1 0.93 min D1H-imidazo[4,5-c]quinolin-2-yl]methyl}-N-ethylacetamide 478N-{[4-amino-1-(2-hydroxyethyl)-7-(1H-pyrazol-1-yl)- 408.1 1.00 min D1H-imidazo[4,5-c]quinolin-2-yl]methyl}- N-ethylpropanamide 479N-{[4-amino-1-ethyl-7-(1H-pyrazol-1-yl)-1H-imidazo 378.0 1.12 min E[4,5-c]quinolin-2-yl]methyl}-N-ethylacetamide 480N-{[4-amino-1-ethyl-7-(thiophen-2-yl)-1H-imidazo 408.0 1.50 min E[4,5-c]quinolin-2-yl]methyl}-N-ethylpropanamide 481N-{[4-amino-1-ethyl-7-(1H-pyrazol-1-yl)-1H-imidazo 392.2 1.33 min C[4,5-c]quinolin-2-yl]methyl}-N-ethylpropanamide 482N-{[4-amino-1-(2-hydroxyethyl)-7-(thiophen-2-yl)- 410.1 1.79 min D1H-imidazo[4,5-c]quinolin-2-yl]methyl}-N-ethylacetamide LC Methods forTable 4: A: Column: Waters XBridge C18, 2.1 mm × 50 mm, 1.7 μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammoniumacetate; Temperature: 50° C.; Gradient: 0% B to 100% B over 3 min, thena 0.75 min hold at 100% B; Flow: 1 mL/min. B: Column: Waters AcquityUPLC BEH C18, 2.1 × 50 mm, 1.7-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10 mM ammonium acetate; Temperature: 50° C.;Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B;Flow: 1.0 mL/min. C: Column: Shim-pack XR-ODS 3.0 mm × 50 mm, 2.2 μmparticles; Mobile Phase A: water with 0.05% TFA; Mobile Phase B:acetonitrile with 0.05% TFA; Temperature: 40° C.; Gradient: 0% B to 95%B over 2 min, then a 0.7 min hold at 95% B; Flow: 1.5 mL/min. D: Column:Kinetex EVO, 3.0 mm × 50 mm, 2.6 μm particles; Mobile Phase A: waterwith 0.03% NH3H2O; Mobile Phase B: acetonitrile; Temperature: 40° C.;Gradient: 10% B to 95% B over 2 min, then a 0.60 min hold at 95% B;Flow: 1.2 mL/min. E: Column: XBridge BEH Shield RP18, 2.1 mm × 50 mm,2.5 μm particles; Mobile Phase A: water with 6.5 mM ammoniumbicarbonate; Mobile Phase B: acetonitrile; Temperature: 40° C.;Gradient: 10% B to 50% B over 2.2 min, then to 95% B over 0.60 min, then0.70 min hold at 95% B; Flow: 1 mL/min

Example 5: Example Preparation Method of Analogs Wherein R¹/R²=Lactamand R⁵=Aryl

Step 1. Preparation of1-((7-bromo-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-2-yl)methyl)pyrrolidin-2-one

To a solution of 7-bromo-N⁴-(4-methoxybenzyl)-quinoline-3, 4-diamine (1g, 2.8 mmol) and (2-oxo-pyrrolidin-1-yl)-acetic acid (0.450 g, 3.15mmol)) in DMF (10 mL) was added HATU (1.4 g, 3.68 mmol) and NEt₃ (0.78mL, 5.6 mmol). The mixture was stirred at room temperature for 2 hoursand then heated in a 60° C. oil bath for 24 hours. The cooled reactionmixture was concentrated to remove all volatiles. Water (30 mL) wasadded and the precipitate was filtered and dried to give crude1-((7-bromo-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-2-yl)methyl)pyrrolidin-2-onewhich was used in the next step without further purification. (1.4g, >100% yield) (ES, m/z): [M+H]⁺=465.2/467.1

Step 2. Preparation of7-bromo-1-(4-methoxybenzyl)-2-((2-oxopyrrolidin-1-yl)methyl)-1H-imidazo[4,5-c]quinoline5-oxide

To a solution of1-((7-bromo-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-2-yl)methyl)pyrrolidin-2-one(370 mg, 1.01 mmol) in CHCl₃ (10 mL) was added m-chloroperoxybenzoicacid (70% grade, 263 mg, 1.5 mmol). The mixture was stirred for 60° C.for 3 hours at which time the cooled mixture was diluted with asaturated aqueous solution of NaHCO₃ and extracted with CH₂Cl₂ (2×20mL). The combined organic layers were washed with brine, dried overNa₂SO₄, filtered, and concentrated to give the crude N-oxide (400 mg,1.05 mmol, 99%) as a brownish foam. (ES, m/z): [M+H]⁺=481.2/483.1

Step 3. Preparation of1-((4-amino-7-bromo-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-2-yl)methyl)pyrrolidin-2-one

To a solution of7-bromo-1-(4-methoxybenzyl)-2-((2-oxopyrrolidin-1-yl)methyl)-1H-imidazo[4,5-c]quinoline5-oxide (400 mg, 1.05 mmol) and NH₄OH (10 mL) in dichloromethane (20 mL)cooled in an ice water bath, was added p-toluenesulfonyl chloride (300mg, 1.57 mmol) in CH₂Cl₂ (10 mL) dropwise. The resulting solution wasstirred another 30 min after complete addition. Water (20 mL) was addedand the layers were separated. The aqueous layer was extracted one moretime with CH₂Cl₂ (30 mL). The solution was filtered through a pad ofNa₂SO₄ and the filtrate was concentrated in vacuo. The residue wastriturated with EtOAc/hexanes (1/3) and dried under high vacuum toafford1-((4-amino-7-bromo-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-2-yl)methyl)pyrrolidin-2-oneas a yellow solid (317 mg, 0.66 mmol, 66%). (ES, m/z):[M+H]⁺=480.3/482.2

Step 4. Preparation of 1-((4-amino-1-(4-methoxybenzyl)-7-aryl(heteroaryl)-1H-imidazo[4,5-c]quinolin-2-yl)methyl)pyrrolidin-2-one

To a dioxane solution of1-((4-amino-7-bromo-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-2-yl)methyl)pyrrolidin-2-one(400 mg, 833 μmol) was added an aryl (heteroaryl) boronic acid (orarylboronate ester) (1.5 equiv), Pd(dppf)Cl₂.CH₂Cl₂ (50 mg), and anaqueous solution of K₂CO₃ (10 mL, 2M) sequentially. The mixture wasirradiated in a Biotage Initiator microwave apparatus at 120° C. for 10min. The organic layer was diluted with EtOAc and separated, and theaqueous layer was washed with EtOAc. The combined organic layers werefiltered, evaporated and flash chromatographed on silica gel elutingwith chloroform/methanol to afford pure1-((4-amino-1-(4-methoxybenzyl)-7-aryl(heteroaryl)-1H-imidazo[4,5-c]quinolin-2-yl)methyl)pyrrolidin-2-one.

Step 5. General Procedure for Deprotection

The product from the previous step was dissolved in TFA (20 mL) andstirred at 70° C. for 1 hour, at which time LCMS analysis indicated thatthe PMB protecting group was completely cleaved. The mixture wasevaporated and flash chromatographed on silica gel eluting withchloroform/methanol to furnish the product as a free base. The materialwas dissolved in a methanolic solution of hydrogen chloride (1 N), thesolvent evaporated, and the resulting solid washed with diethyl etherand dried to afford 1-((4-amino-7-aryl(heteroaryl)-1H-imidazo[4,5-c]-quinolin-2-yl)methyl)pyrrolidin-2-one asthe hydrochloride salt.

The compounds depicted in Table 6 were made according to the abovesynthetic procedures.

TABLE 6 Compound NAME [M + H]+ 2791-[(4-amino-7-pyridin-3-yl-1H-imidazo[4,5-c]quinolin-2-yl) 359.1methyl]pyrrolidin-2-one 2801-[(4-amino-7-phenyl-1H-imidazo[4,5-c]quinolin-2-yl)methyl] 358.2pyrrolidin-2-one 2811-[[4-amino-7-(2-chlorophenyl)-1H-imidazo[4,5-c]quinolin-2-yl] 392.1methyl]pyrrolidin-2-one 2821-[[4-amino-7-(2-methylphenyl)-1H-imidazo[4,5-c]quinolin-2-yl] 372.2methyl]pyrrolidin-2-one 2831-[[4-amino-7-(2-methoxyphenyl)-1H-imidazo[4,5-c]quinolin-2-yl] 388.2methyl]pyrrolidin-2-one 2841-[[4-amino-7-(2-fluorophenyl)-1H-imidazo[4,5-c]quinolin-2-yl] 376.1methyl]pyrrolidin-2-one 2851-[[4-amino-7-(3-chlorophenyl)-1H-imidazo[4,5-c]quinolin-2-yl] 392.1methyl]pyrrolidin-2-one 2861-[[4-amino-7-(3-methylphenyl)-1H-imidazo[4,5-c] 372.2quinolin-2-yl]methyl]pyrrolidin-2-one 2871-[[4-amino-7-(3-methoxyphenyl)-1H-imidazo[4,5-c] 388.2quinolin-2-yl]methyl]pyrrolidin-2-one 2883-[4-amino-2-[(2-oxopyrrolidin-l-yl)methyl]-1H-imidazo[4,5-c] 383.1quinolin-7-yl]benzonitrile 2891-[[4-amino-7-(3-fluorophenyl)-1H-imidazo[4,5-c]quinolin-2-yl] 376.1methyl]pyrrolidin-2-one 2911-[[4-amino-7-(4-methylphenyl)-1H-imidazo[4,5-c] 372.2quinolin-2-yl]methyl]pyrrolidin-2-one 2921-[[4-amino-7-(4-methoxyphenyl)-1H-imidazo[4,5-c] 388.2quinolin-2-yl]methyl]pyrrolidin-2-one 2941-[(4-amino-7-bromo-1H-imidazo[4,5-c]quinolin-2-yl) 360.0methyl]pyrrolidin-2-one 2951-[(4-amino-7-pyrazol-1-yl-1H-imidazo[4,5-c]quinolin-2-yl) 348.1methyl]pyrrolidin-2-one 2961-[[4-amino-7-(4-methylpyrazol-1-yl)-1H-imidazo[4,5-c] 362.2quinolin-2-yl]methyl]pyrrolidin-2-one 2981-[[4-amino-7-(oxan-4-yl)-1H-imidazo[4,5-c]quinolin-2-yl] 366.2methyl]pyrrolidin-2-one 3011-[[4-amino-7-(3-methylpyrazol-1-yl)-1H-imidazo[4,5-c] 362.2quinolin-2-yl]methyl]pyrrolidin-2-one 3021-[(4-amino-7-cyclohexyl-1H-imidazo[4,5-c]quinolin-2-yl) 364.2methyl]pyrrolidin-2-one 3031-[1-(4-amino-7-bromo-1H-imidazo[4,5-c]quinolin-2-yl)ethyl] 374.1pyrrolidin-2-one 3041-[[4-amino-7-(6-methoxypyridin-3-yl)-1H-imidazo[4,5-c] 389.2quinolin-2-yl]methyl]pyrrolidin-2-one 3071-[[4-amino-7-(2-fluoropyridin-3-yl)-1H-imidazo[4,5-c] 377.1quinolin-2-yl]methyl]pyrrolidin-2-one 3081-[(4-amino-7-thiophen-3-yl-1H-imidazo[4,5-c]quinolin-2-yl) 364.1methyl]pyrrolidin-2-one 3091-[(4-amino-7-thiophen-2-yl-1H-imidazo[4,5-c]quinolin-2-yl) 364.1methyl]pyrrolidin-2-one 3152-[4-amino-2-[(2-oxopyrrolidin-l-yl)methyl]-1H-imidazo[4,5-c] 383.2quinolin-7-yl]benzonitrile 3161-[(4-amino-7-bromo-1H-imidazo[4,5-c]quinolin-2-yl) 436.1methyl]-4-phenylpyrrolidin-2-one 3191-[[4-amino-7-(2-methoxypyridin-3-yl)-1H-imidazo[4,5-c] 389.2quinolin-2-yl]methyl]pyrrolidin-2-one 3201-[[4-amino-7-(2-chloropyridin-3-yl)-1H-imidazo[4,5-c] 393.1quinolin-2-yl]methyl]pyrrolidin-2-one 3211-[[4-amino-7-(4-chloropyridin-3-yl)-1H-imidazo[4,5-c] 393.1quinolin-2-yl]methyl]pyrrolidin-2-one 3241-[[4-amino-746-(trifluoromethyppyridin-3-yl]-1H- 427.1imidazo[4,5-c]quinolin-2-yl]methyl]pyrrolidin-2-one 3265-[4-amino-2-[(2-oxopyrrolidin-l-yl)methyl]-1H-imidazo[4,5-c] 384.1quinolin-7-yl]pyridine-3-carbonitrile 3275-[4-amino-2-[(2-oxopyrrolidin-l-yl)methyl]-1H-imidazo[4,5-c] 384.1quinolin-7-yl]pyridine-2-carbonitrile 3281-[[4-amino-7-(5-chloropyridin-3-yl)-1H-imidazo[4,5-c] 393.1quinolin-2-yl]methyl]pyrrolidin-2-one 3301-[[4-amino-7-(6-fluoropyridin-3-yl)-1H-imidazo[4,5-c] 377.1quinolin-2-yl]methyl]pyrrolidin-2-one 3311-[[4-amino-7-(5-fluoropyridin-3-yl)-1H-imidazo[4,5-c] 377.1quinolin-2-yl]methyl]pyrrolidin-2-one 3321-[(4-amino-7-cycloheptyl-1H-imidazo[4,5-c]quinolin-2-yl) 378.2methyl]pyrrolidin-2-one 3331-[(4-amino-7-pyridin-3-yl-1H-imidazo[4,5-c]quinolin-2-yl) 435.2methyl]-4-phenylpyrrolidin-2-one

The compounds depicted in Table 7 were made according to the abovesynthetic procedures.

TABLE 7 LC/MS LC Compound Name [M⁺ + H] LC RT Method 4631-{[4-amino-1-ethyl-7- 392.2 1.16 min C (thiophen-2-yl)-1H-imidazo[4,5-c]quinolin-2-yl]methyl} pyrrolidin-2-one 465 1-{[4-amino-1-ethyl-7-376.2 0.98 min C (1H-pyrazol-1-yl)-1H- imidazo[4,5-c]quinolin-2-yl]methyl}pyrrolidin-2-one 466 1-{[4-amino-1-ethyl-7- 376.2 0.95 min C(1H-pyrazol-5-yl)-1H- imidazo[4,5-c]quinolin-2-yl]methyl}pyrrolidin-2-one 469 1-{[4-amino-1-(2-hydroxyethyl)- 408.0 1.16min A 7-(thiophen-2-yl)-1H-imidazo [4,5-c]quinolin-2-yl]methyl}pyrrolidin-2-one LC Methods: A: Column: Kinetex EVO, 3.0 mm × 50 mm, 2.6μm particles; Mobile Phase A: water with 5 mM ammonium bicarbonate;Mobile Phase B: acetonitrile; Temperature: 40° C.; Gradient: 10% B to95% B over 2 min, then a 0.79 min hold at 95% B; Flow: 1 mL/min; B:Column: Kinetex EVO, 3.0 mm × 50 mm, 2.6 μm particles; Mobile Phase A:water with 0.03% NH3H2O; Mobile Phase B: acetonitrile; Temperature: 40°C.; Gradient: 10% B to 95% B over 2 min, then a 0.60 min hold at 95% B;Flow: 1.2 mL/min; C: Column: Express C18 2.1 mm × 50 mm, 2.7 μmparticles; Mobile Phase A: water with 0.05% TFA; Mobile Phase B:acetonitrile with 0.05% TFA; Temperature: 40° C.; Gradient: 5% B to 100%B over 2 min, then a 0.75 min hold at 100% B; Flow: 0.8 mL/min

Example 6: Biological Assays Measurement of IL-1β Production inPMA-Differentiated THP-1 Cells

THP-1 cells were purchased from the American Type Culture Collection andsub-cultured according to instructions from the supplier. Prior toexperiments, cells were cultured in RPMI 1640 containing 10% heatinactivated FBS, penicillin (100 units/ml) and streptomycin (100 μg/ml),and maintained in log phase prior to experimental setup. Prior to theexperiment THP-1 were treated with PMA (Phorbol 12-myristate 13-acetate)(10 μg/ml) for 24 hours. The day of the experiment the media was removedand attaching cells were treated with trypsin for 2 minutes, cells werethen collected, washed with PBS (phosphate buffer saline), spin down,resuspended in 2% heat inactivated FBS with RPMI at a concentration of1×10⁶ cells/ml, and 100 μl was plated in a 96 well plate. Compounds weredissolved in dimethyl sulfoxide (DMSO) and added to the culture mediumto achieve desired concentration (e.g. 100, 30, 10, 3, 1, 0.3 or 0.1μM). Cells were incubated with compounds for 4 hours. Cell freesupernatant was collected and the production of IL-1β was evaluated byELISA. A vehicle only control was run concurrently with each experiment.Final DMSO concentration was 1%. Compounds exhibit a dose-relatedincrease of IL-1β production in PMA-differentiated THP-1 cells.

Measurement of IL-1β Production in PMA-Differentiated THP-1 Cells(Alternative Procedure)

THP-1 cells were purchased from the American Type Culture Collection andsub-cultured according to instructions from the supplier. Prior toexperiments, cells were cultured in RPMI 1640 containing 10% heatinactivated FBS, penicillin (100 units/ml), streptomycin (100 μg/ml),HEPES (10 mM) and sodium pyruvate (1 mM) and maintained in log phaseprior to experimental setup. Prior to the experiment, THP-1 cells weretreated with PMA (Phorbol 12-myristate 13-acetate) (20 μg/ml) overnight.The day of the experiment, the media was removed and attached cells weretreated with trypsin for 2 minutes, cells were then collected, washedwith PBS (phosphate buffer saline), pelleted by centrifugation andresuspended in 2% heat inactivated FBS with RPMI at a concentration of50,000 cells/well in a 384 well plate. Cell free supernatant wascollected and the production of IL-1β was evaluated by ELISA. Compoundswere dissolved in dimethyl sulfoxide (DMSO) and added to the culturemedium to achieve desired concentration (e.g. 100, 30, 10, 3, 1, 0.3 or0.1 μM). Cells were incubated with compounds for 2 hours. A vehicle onlycontrol was run concurrently with each experiment. Final DMSOconcentration was 1%. Compounds exhibit a dose-related increase of IL-1βproduction in PMA-differentiated THP-1 cells.

Measurement of IL-1β Production—hTRF Protocol (Second AlternativeProcedure)

Serial dilutions of compounds in DMSO were added to low volume 384 wellplates at 100 nl/well using an ECHO 550 acoustic dispenser (Labcyte) toachieve final starting concentration of 10 μM in assay.

THP-1 cells in RPMI (Gibco, 11875) media with 10% FBS at a density of1×10⁶ cell/ml in a T175 flask were treated with a final concentration ofphorbol 12-myristate 13-acetate (PMA) (Sigma, P1585) of 50 ng/mlovernight at 37° C. at 5% CO₂ for differentiation. Cells were harvestedthe next day after rinsing well with dPBS using 0.5% trypsin. A cellsolution was prepared of 1×10⁶ cells/ml for 50,000 cells in 50 μl/wellin RPMI media with 2% FBS. Cells were plated using a multichannelpipette onto the compound dilutions in Greiner, 384 well, black clearbottom tissue culture treated plates (781090). The plates were incubatedin 37° C. incubator at 5% CO₂ for 2 hours.

After the 2 hour incubation, the cell plates were spun in the centrifugefor 5 minutes at 1200 rpm. Using the Felix (CyBio), 8 μl of thesupernatant was transferred to 384 well, low volume, white proxy plates.(Perkin Elmer, 6008230). A human IL1beta hTRF kit was used to analyzethe supernatant (CISBIO, 62HIL1BPEG). The kit instructions were followedfor preparing the IL1Beta standard curve and then the antibodies fromthe kit were diluted 1:40 rather than 1:20 as kit instructed. Oncecombined, the antibodies were added across the plates, 5 μl/well. Theplates were sealed and incubated at 4° C. overnight. The plates werethen read on the Perkin Elmer EnVision at 665/615 nm using the hTRFlaser. Compounds exhibited a dose-related increase of IL-1β production.

Measurement of IL-1β Production—Human Whole Blood Assay

Serial dilutions of compounds in DMSO were added to low volume 384 wellplates at 100 nl/well using an ECHO 550 acoustic dispenser (Labcyte) toachieve final starting concentration of 10 uM in assay.

Human venous whole blood obtained from healthy donors was pre-treatedwith LPS (Invivogen, Cat #tlrl-eblps) at 1 ng/ml for four hours at 37°C. in a humidified 95% air/5% CO2 incubator. Primed blood was added tothe compound plate and incubated for additional 4 hours at 37° C.IL-1beta in the supernatants was measured using AlphLISA kit (Cat#AL220) according to manufacturer's instructions. Compounds exhibited adose-related increase of IL-1β production. EC50 was determined usingprimed but untreated blood as baseline.

Measurement of IL-1β Production—Mouse hTRF Protocol

Immortalized mouse macrophages derived from C57BL/6 mice were obtainedfrom Ericke Latz, University of Bonn/University of MassachusettsWorchester, Mass. The cells were harvested using 0.05% Trypsin andwashed with PBS. Cell were plated at 30,000 cells per well in 25 ul inDMEM (Gibco, 11965) supplemented with 2% FBS and incubated for 10minutes at 37° C. at 5% CO2. LPS-EB (Invivogen, tlr-eblps) was added toa final concentration of 200 ng/ml at 5 ul/well and cells were incubatedfor 2 hours at 37° C. at 5% CO2.

Serial dilutions of compounds in DMSO were added to cells in low volume384 well plates at 60 nl/well using an ECHO 550 acoustic dispenser(Labcyte) to achieve final starting concentration of 50 uM in assay andincubated with compounds for additional 2 hours at 37° C. at 5% CO2.

After the 2 hour incubation, the cell plates were spun in the centrifugefor 5 minutes at 1200 rpm. Using the Felix (CyBio), 8 ul of thesupernatant was transferred to 384 well, low volume, white proxy plates.(Perkin Elmer, 6008230). A human IL1beta hTRF kit was used to analyzethe supernatant (CISBIO, 62MIL1BPEH). The kit instructions were followedfor preparing the IL1Beta standard curve (the antibodies from the kitwere diluted 1:40 rather than 1:20 as kit instructed). Once combined,the antibodies were added across the plates at 5 ul/well. The plateswere sealed and incubated at 4° C. overnight. The plates were read onthe Perkin Elmer EnVision at 665/615 nm using the hTRF laser. Data wasthen converted to pg/ml of Il1Beta. Compounds exhibited a dose-relatedincrease of IL-1β production.

In Vitro Human TLR7 and TLR8 Binding Reporter Assays

Logarithmically-growing human HEK-Blue cells co-expressing a TLR7 orTLR8 gene and a NF-kB/AP1-inducible SEAP (secreted embryonic alkalinephosphatase; Invivogen, San Diego, Calif.) reporter gene are added toindividual wells of a 384-well plate (15,000 cells per 20 μL per well)and maintained for 24 h at 37° C., 5% CO₂. Test compounds or DMSO aredistributed to separate wells the next day using acoustic liquidhandling technology (100 nL per well) and cells are subsequentlyincubated for 18 h at 37° C., 5% CO₂. Cellular SEAP production ismeasured using an Envision plate reader instrument thirty minutes afteradding freshly-made Quanti-Blue reagent (prepared by followingmanufacturer instructions; Invivogen, San Diego, Calif.) to the HEK-BlueTLR Nf-kB-SEAP cell reactions. All EC₅₀ values (half-maximal effectiveconcentration) are determined using proprietary data analysis software.Normalized EC₅₀ value=absolute value determined by setting 100% Ymaxusing a reference standard RLU (relative light unit) values from cellstreated with 50 μM of the reference standard.

In Vivo Pharmacology

Compounds are assessed for in vivo efficacy in preclinical syngeneictumor models such as MC38, CT26 and 4T1 respectively. The tumor linesare implanted subcutaneously in syngeneic, immunocompetent mice. Forintra-tumoral (IT) route of compound administration abscopal tumormodels are utilized. In the abscopal model mice are subcutaneouslyinjected with 0.1 mL cells (1×107 cells/ml) into the right and leftflank respectively, using a 1 mL tuberculin syringe with a 25 g needle.Tumored animals are sorted and randomized when tumors on each side reachapproximately 100 mm3. The compounds are administered with an ITinjection in the right flank at appropriate doses and dosing frequencyeither alone or in combination with checkpoint blockers such asanti-PD-1 and/or anti-CTLA4. For combination studies the checkpointblockers are administered intraperitoneally (IP) at optimal doses anddosing frequency. Efficacy is determined by monitoring the tumor volumesof the injected and abscopal tumor respectively.

Additional studies are carried out in the abscopal tumor models todetermine the PK/PD relationship as well as to assess the profile oftumor-infiltrating lymphocytes (TILs). Other routes of administration,such as intravenous or intramuscular, are explored along with variousdosing regimens to determine the dosing routes and regimen that provideoptimal efficacy.

Table 1 depicted above includes biological data of compounds that wereassayed using one or more of the above procedures.

A number of embodiments of the invention have been described.Nevertheless, it will be understood that various modifications may bemade without departing from the spirit and scope of the invention.Accordingly, other embodiments are within the scope of the followingclaims.

What is claimed is:
 1. A method of treating cancer, comprisingadministering to a subject in need of such treatment an effective amountof a compound of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein: R¹ isindependently unsubstituted C₁₋₆ alkyl or C(═O)R^(a); R² isindependently H or unsubstituted C₁₋₆ alkyl; R³ is: (i) H; (ii)unsubstituted C₁₋₂ alkyl; or (iii) X—R⁸, wherein X is an unbranched C₁₋₆alkylene, and R⁸ is —OH, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, CO₂R^(a), or—CONR^(c)R^(d); R⁴ is independently H or halo; R⁵ is independentlyselected from: (i) C₃₋₆ cycloalkyl substituted with 0 to 2 R^(f); (ii)phenyl substituted with 0 to 3 R^(g); (iii) heteroaryl including from 5to 6 ring atoms, wherein from 1 to 3 ring atoms are each independentlyselected from: N, NH, O, and S, wherein the heteroaryl is substitutedwith 0 to 3 R^(g); (iv) C₁₋₆ alkyl substituted with 0 to 2 R^(h); and(v) C₅₋₆ cycloalkenyl substituted with 0 to 2 R^(f); R^(a) is: (i) C₁₋₆alkyl substituted with 0 to 2 R^(h), (ii) —(C₀₋₃ alkylene)-C₃₋₆cycloalkyl, wherein the cycloalkyl is substituted with 0 to 2 R^(f);(iii) —(C₁₋₃ alkylene)-heterocyclyl including from 5 to 6 ring atoms,wherein from 1 to 3 ring atoms are each independently selected fromN(R^(e)), O, and S, wherein the heterocyclyl is substituted with 0 to 4independently selected R^(f); (iv) —(C₀₋₃ alkylene)-phenyl substitutedwith 0 to 4 independently selected R^(g); or (v) —(C₀₋₃alkylene)-heteroaryl including from 5 to 10 ring atoms, wherein from 1to 4 ring atoms are each independently selected from N, N(R^(e)), O, andS, wherein the heteroaryl is substituted with 0 to 3 independentlyselected R^(g); each occurrence of R^(c) and R^(d) is independently H orC₁₋₄ alkyl; each occurrence of R^(e) is independently H or C₁₋₄ alkyl;each occurrence of R^(f) is independently C₁₋₆ alkyl, C₁₋₄ haloalkyl,—OH, F, Cl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, or cyano; each occurrence ofR^(g) is independently halo, cyano, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, or C₁₋₄ haloalkoxy; and each occurrence of R^(h) isindependently —OH, F, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, or cyano.
 2. Themethod of claim 1, wherein the compound is of Formula (II) or apharmaceutically acceptable salt thereof, wherein: R² is independently Hor unsubstituted C₁₋₃ alkyl; R³ is H, unsubstituted C₁₋₂ alkyl, or X—R⁸,wherein X is an unbranched C₂₋₄ alkylene, and R⁸ is CO₂R^(a), or—CONR^(c)R^(d); and R^(a) is H, C₁₋₄ alkyl substituted with 0 to 1_OH,C₃₋₆ cycloalkyl, phenyl, or heteroaryl including from 5 to 6 ring atoms,wherein from 1 to 4 ring atoms are each independently selected from N,N(R^(e)), O, and S.
 3. The method of claim 2, wherein the compound is ofFormula (II) or a pharmaceutically acceptable salt thereof, wherein: R²is independently H, CH₃ or CH₂CH₃; R³ is H, CH₃, or —(CH₂)₃C(═O)OCH₃; R⁵is independently CH₃, cyclopentyl, cyclopentenyl, phenyl, pyrazol-1-yl,or pyrazol-3-yl; and R^(a) is H, CH₃, CH₂CH₃, CH(CH₃)₂, C(CH₃)₃,cyclopropyl, or thiazolyl.
 4. The method of claim 3, wherein thecompound is of Formula (II) or a pharmaceutically acceptable saltthereof, wherein: R² is independently H, CH₃ or CH₂CH₃; R³ is H or CH₃;R⁵ is independently CH₃, cyclopentyl, cyclopentenyl, phenyl,pyrazol-1-yl, or pyrazol-3-yl; and R^(a) is CH₃, CH₂CH₃, CH(CH₃)₂,C(CH₃)₃, or cyclopropyl.
 5. The method of claim 1, wherein the compoundis of Formula (II) or a pharmaceutically acceptable salt thereof,wherein: R¹ is C(═O)R^(a); R² is independently H, CH₃ or CH₂CH₃; R³ isindependently H, CH₃, CH₂CH₃ or CH₂CH₂OH; R⁴ is H; R⁵ is independentlycyclopentyl, cyclopentenyl, thienyl, pyrazol-1-yl, pyrazol-3-yl,pyrazol-5-yl or (phenyl substituted with 0-1 C₁₋₄ alkyl); and R^(a) isCH₃, CH₂CH₃, CH(CH₃)₂, C(CH₃)₃, —(CH)₂CH(CH₃)₂, cyclopropyl,1-methyl-1H-pyrrol-2-yl, or (phenyl substituted with C₁₋₄ alkoxy or Cl).6. The method of claim 1, wherein the compound is of Formula (II) or apharmaceutically acceptable salt thereof, wherein: R¹ is independentlyCH₃, CH₂CH₃, CH(CH₃)₂, or C(CH₃)₃; R² is independently H, CH₃ or CH₂CH₃;R³ is independently H, CH₃ or CH₂CH₃; R⁴ is H; and R⁵ is independentlypyrazol-1-yl, pyrazol-3-yl or pyrazol-5-yl.
 7. A method of treatingcancer, comprising administering to a subject in need of such treatmentan effective amount of a compound selected from:

or a pharmaceutically acceptable salt thereof.
 8. The method of claim 1,wherein the cancer is selected from acute myeloid leukemia,adrenocortical carcinoma, Kaposi sarcoma, lymphoma, anal cancer,appendix cancer, teratoid/rhabdoid tumor, basal cell carcinoma, bileduct cancer, bladder cancer, bone cancer, brain cancer, breast cancer,bronchial tumor, carcinoid tumor, cardiac tumor, cervical cancer,chordoma, chronic lymphocytic leukemia, chronic myeloproliferativeneoplasm, colon cancer, colorectal cancer, craniopharyngioma,endometrial cancer, ependymoma, esophageal cancer,esthesioneuroblastoma, Ewing sarcoma, eye cancer, fallopian tube cancer,gallbladder cancer, gastrointestinal carcinoid tumor, gastrointestinalstromal tumor, germ cell tumor, hairy cell leukemia, head and neckcancer, heart cancer, liver cancer, hypopharngeal cancer, pancreaticcancer, kidney cancer, laryngeal cancer, chronic myelogenous leukemia,lip and oral cavity cancer, lung cancer, melanoma, Merkel cellcarcinoma, mesothelioma, mouth cancer, oral cancer, osteosarcoma,ovarian cancer, penile cancer, pharyngeal cancer, prostate cancer,rectal cancer, salivary gland cancer, skin cancer, small intestinecancer, soft tissue sarcoma, testicular cancer, throat cancer, thyroidcancer, urethral cancer, uterine cancer, vaginal cancer, and vulvarcancer.
 9. The method of claim 1, wherein the cancer is a refractorycancer.
 10. The method of claim 1, wherein the cancer is selected frombreast cancer, colon cancer, rectal cancer, colorectal cancer,pancreatic cancer, and prostate cancer.
 11. The method of claim 1,wherein the cancer is selected from hormone receptor positive breastcancer, microsatellite stable colon or rectal cancer, pancreatic cancerand prostate cancer.
 12. The method of claim 1, wherein the compound isadministered in combination with one or more additional cancertherapies.
 13. The method of claim 12, wherein the one or moreadditional cancer therapies comprise surgery, radiotherapy,chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy,or a combination thereof.
 14. The method of claim 12, wherein theadditional cancer therapy comprises one or more agents selected fromnivolumab, pembrolizumab, PDR001, MEDI-0680, cemiplimab, JS001,BGB-A317, INCSHR1210, TSR-042, GLS-010, AM-0001, STI-1110, AGEN2034,MGD013, IBI308, BMS-936559, atezolizumab, durvalumab, avelumab,STI-1014, CX-072, LY3300054, CK-301, urelumab, PF-05082566, MEDI6469,TRX518, varlilumab, CP-870893, BMS-986016, MGA271, lirilumab, IPH2201,emactuzumab, INCB024360, galunisertib, ulocuplumab, BKT140, Bavituximab,CC-90002, bevacizumab, MNRP1685A, ipilimumab, MK-1308, AGEN-1884, andtremelimumab.
 15. The method of claim 12, wherein the additional cancertherapy comprises one or more agents selected from nivolumab,ipilimumab, pembrolizumab, atezolizumab, durvalumab and avelumab. 16.The method of claim 1, wherein the compound is administeredintratumorally.
 17. The method of claim 1, wherein the compound isadministered systemically.
 18. The method of claim 1, wherein the methodfurther comprises identifying the subject.
 19. The method of claim 1,wherein the subject is a human.
 20. The method of claim 1, wherein thecancer is selected from acute myeloid leukemia, lymphoma, bladdercancer, brain cancer, breast cancer, cervical cancer, chroniclymphocytic leukemia, colon cancer, colorectal cancer, esophagealcancer, eye cancer, gastrointestinal carcinoid tumor, gastrointestinalstromal tumor, head and neck cancer, liver cancer, pancreatic cancer,kidney cancer, laryngeal cancer, chronic myelogenous leukemia, lip andoral cavity cancer, lung cancer, melanoma, mouth cancer, oral cancer,ovarian cancer, prostate cancer, rectal cancer, skin cancer, smallintestine cancer, testicular cancer, throat cancer, urethral cancer,uterine cancer, vaginal cancer, and vulvar cancer.
 21. The method ofclaim 1, wherein the cancer is selected from acute myeloid leukemia,lymphoma, bladder cancer, brain cancer, breast cancer, cervical cancer,chronic lymphocytic leukemia, colon cancer, colorectal cancer,esophageal cancer, eye cancer, gastrointestinal carcinoid tumor,gastrointestinal stromal tumor, head and neck cancer, liver cancer,pancreatic cancer, kidney cancer, chronic myelogenous leukemia, lungcancer, melanoma, ovarian cancer, prostate cancer, rectal cancer, skincancer, small intestine cancer, testicular cancer, urethral cancer,uterine cancer, vaginal cancer, and vulvar cancer.
 22. The method ofclaim 20, wherein the cancer is selected from breast cancer, cervicalcancer, colon cancer, colorectal cancer, esophageal cancer, head andneck cancer, liver cancer, pancreatic cancer, kidney cancer, lungcancer, melanoma, ovarian cancer, prostate cancer, rectal cancer, skincancer, urethral cancer, and uterine cancer.
 23. The method of claim 22,wherein the cancer is selected from breast cancer, colorectal cancer,melanoma, head and neck cancer, skin cancer and prostate cancer.
 24. Themethod of claim 22, wherein the cancer is head and neck cancer.